Peptoids and Polypeptoids at the Frontier of Supra - American

Review pubs.acs.org/CR

Peptoids and Polypeptoids at the Frontier of Supra- and Macromolecular Engineering Niklas Gangloff,† Juliane Ulbricht,†,§ Thomas Lorson,†,§ Helmut Schlaad,‡ and Robert Luxenhofer*,† †

Functional Polymer Materials, Chair for Chemical Technology of Materials Synthesis, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany ‡ Institute of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany 3.2.4. Computational Modeling 3.3. Mimicking Tertiary Structures 3.3.1. Globular Structures 3.3.2. Multihelical Bundles 3.4. Mimicking Quaternary Structures 3.4.1. Peptoid Nanosheets 3.4.2. Peptoid Superhelices 3.4.3. Nanotubes and Round-Bottom Flasks 3.4.4. Amylin-Like Structures, Microspheres, and Worm-Like Micelles 4. Applications of (Poly)peptoids 4.1. (Poly)peptoids as Biomaterials 4.1.1. Biocompatibility and Degradability 4.1.2. Drug Delivery 4.1.3. Pharmacologically Active (Poly)peptoids 4.1.4. Nonfouling Surface Coatings 4.2. Energy Materials 4.3. Crystallization Modifiers 4.3.1. Kinetic Hydrate Inhibitors 4.3.2. Antifreeze Agents 4.3.3. Controlling Biomineralization 4.4. Chromatography Materials 4.5. Phase Transfer Catalyst and Ion Binding Peptoids 5. Summary and Outlook: The Frontier Author Information Corresponding Author Author Contributions Notes Biographies Acknowledgments References

CONTENTS 1. Introduction and Historical Perspective 2. Synthesis and Characterization of (Poly)peptoids 2.1. Ring-Opening Polymerization 2.1.1. Side Chain Variations 2.1.2. Polymerization Kinetics 2.1.3. Polymerization of N-Thiocarboxyanhydrides 2.1.4. Copolymerization of N-Carboxyanhydrides 2.1.5. (Poly)(β-peptoid)s and (Poly)(γ-peptoid)s 2.2. Solid-Phase Syntheses toward Highly Defined (Poly)peptoids 2.2.1. Stepwise Synthesis from Solid Supports 2.2.2. Ring-Opening Polymerization from Solid Supports 2.2.3. Combinatorial Libraries for Peptoid Ligand Screening 2.3. Ribosomal Synthesis 2.4. Macromolecular Engineering 2.4.1. Cyclic (Poly)peptoids 2.4.2. Branched Polypeptoids and Polypeptoid Brushes 2.4.3. Polymer-Analogue Modification of (Poly)peptoids 2.5. Physico-Chemical Characteristics of Polypeptoids 2.5.1. Properties in Solution 2.5.2. Bulk Properties 3. Intramolecular and Intermolecular Assembly of (Poly)peptoids 3.1. Controlling and Modifying the Primary Structure 3.2. Mimicking Secondary Structures 3.2.1. Controlling cis/trans-Conformation 3.2.2. Helices: Multifaceted Structural Elements 3.2.3. Sheet, Ribbon, Turn, and Loop

© 2015 American Chemical Society

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1. INTRODUCTION AND HISTORICAL PERSPECTIVE In most general terms, polymers and their supramolecular assemblies have been defining life on this planet since its conception. Polymers of nucleic acids carry the code of life and polymers of carbohydrates are probably the most common (per mass) macromolecules on the planet and give macroscopic structure to flora and fauna. Finally, polymers of amino acids translate the genetic code into function.

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Special Issue: Frontiers in Macromolecular and Supramolecular Science

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Received: May 1, 2015 Published: December 23, 2015 1753

DOI: 10.1021/acs.chemrev.5b00201 Chem. Rev. 2016, 116, 1753−1802

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noted the formation of an “insoluble body” after treating glycine-NCA with water and alcohol and correctly analyzed the products as anhydrides of glycine.19 He also reported the first N-substituted glycine-NCA (NNCA), N-phenylglycine-NCA.20 A year later, Leuchs termed the product of hydrolysis of NCAs as polymers.21 However, as Staudinger noted in 1920, the terminology with respect to polymers was not “homogenous” at that time.24 In 1922, Fuchs reported that he discovered an even simpler method to prepare NCAs already in 1910.25 Actually, in this report, Fuchs describes the synthesis of N-phenylglycineNCA and p-tolylglycine-NCA out of alkaline aqueous solution. Fuchs did not hint at the preparation of the corresponding polymers. Curtius states polymeric anhydrides as products of the reaction of NCAs (which Curtius termed isatoic acid anhydrides, or in German “isatosäure-anhydrid”) with aniline and that these were already described by Leuchs.26 Interestingly, Curtius described in a series of papers the synthesis of NCAs via Curtius rearrangement form potassium salts of malonic acids.26−28 The actual isatoic acid anhydride described by Curtius was the first example of a 1,3-oxazinane-2,6-dione derivative, otherwise termed β-amino acid-NCA.27 Wessely and co-workers published a series of papers on reactions of NCAs and NNCAs between 1925 and 1955. It was also noted that amorphous high molecular products were obtained by reaction with aniline. The structures used by Curtius and Wessely to describe the products suggest from a modern perspective that the nature of this polymer was not fully understood at that time (Scheme 1).

The structure of proteins and glycoproteins has served as a blueprint for macromolecular engineering and supramolecular chemistry for many years. Important contributions to the structure of proteins are hydrogen bonding and hydrophobic interactions. At the same time, these contributions are, under unfavorable circumstances, responsible for misfolding and denaturation of proteins, for example, on surfaces or interfaces. This is typically associated with loss of function and may elicit detrimental effects. Accordingly, suppression of the hydrogen bonding, for example by substitution of the amide nitrogen, can have significant effects on the structure of peptides and proteins.1 For example, L-proline, the only proteinogenic secondary amino acid, serves as an important structural guide in proteins. Poly(L-proline) can form two different types of helices (termed poly(L-proline) I and II helix; PPI and PPII).2−8 In the early days of peptide and polypeptide science, nonproteinogenic D-amino acids were often employed to better understand structural aspects of synthetic issues, the enzymatic degradation, and the influence on the structure and conformation. As an alternative, N-substituted amino acids other than proline were employed. N-Methylation of proteinogenic amino acids was studied in particular in the 1960s and 1970s to understand in more detail formation of secondary structures in the absence of hydrogen bonding (Figure 1).9−16

Scheme 1. Reaction of NCAs with Aniline with NCAs As Described By Curtius and Wessely in the Early 1920sa Figure 1. Structure of polypeptides and their structural variations. NSubstituted polypeptides, bearing substituents both at the nitrogen and the C-α have been rarely studied, with the prominent exception of poly(proline), a non-natural polymer of the only natural and proteinogenic amino acid with a secondary α-amine. Oligomers (and polymers) comprising N-substituted glycine as repeating units are termed (poly)peptoids.

a

The structure of the product, termed a polymeric anhydride, shows the differences in graphical depiction or understanding of the products.18,26.

Tonelli reported that the effect of N-methylation extended to the neighboring amino acid.14 This observation has structural implications in copolymers of amino acids and N-substituted glycines. Notably, N-methylation of polymers of alanine and various esters of glutamic acid leads to formation of helices, comparable to the poly(L-proline) helices.9,12,13,15−17 Important to note, the polymerization of N-carboxyanhydrides (NCAs) of N-substituted amino acids is not generally possible. The substitution at the nitrogen atom as well as the C3 atom appears to interfere with the polymerization. The only reported exceptions are the subject matter of this review, the NCAs of Nsubstituted glycines, proline-NCA (and derivatives), and Nmethylalanine-NCA.15 Poly(sarcosine) (PSR), the most simple polypeptoid, was among the early examples of synthetic polymers reported.18 Interestingly, for the most part of the last nine decades, PSR was considered and mainly investigated as a reference for synthetic polypeptides. Synthetic polypeptides were studied even before the concept of macromolecules was accepted by the scientific community in the 1920’s. The researcher who first prepared synthetic polypeptides,19−21 Hermann Leuchs, was working under the fiercest opponent of the concept of macromolecules,22,23 Nobel laureate Emil Fischer. Leuchs

In these early works, Sigmund and Wessely also remarked that NNCAs are conveniently purified by sublimation, whereas NCAs typically need to be recrystallized.18 Wessely also noted, in a systematic study, the effects of treatment of NCAs and NNCAs with water.29 In this early work, Wessely actually differentiated between the polymeric anhydrides obtained by NCA hydrolysis/polymerization and the known polypeptides (of natural origin, i.e., proteins). However, striking similarities with respect to analytical results were also noticed. Interestingly, it was also reported that the monomers are rather stable against ice-cold water, while at room temperature rapid degradation is observed. Many decades later, Poché et al. reported on washing NCAs with ice-cold water as an “unconventional” method to purify NCAs.30 Wessely followed up on his study and eventually used sarcosine-NCA, specifically since the “unpleasant properties” (what Wessely particularly referred to was the insoluble character of polyglycine) of the polymeric anhydride of glycine prevented further characterization.31 The purpose of using sarcosine-NCA was to allow investigation of suspected products of high molar mass. However, Wessely reported that despite this further study, it could not be decided whether polymeric 1754


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Scheme 2. Mechanism of Polymerization of N-Substituted Glycine N-Carboxyanhydrides, Initiated by Primary Amines (Initiator Group and Propagating Species in Red, CO2 in Blue)

anhydrides or polypeptides were the product of the reaction.31 From our perspective, one could argue that the investigation and understanding of polypeptides was developed through polypeptoids. Of course, this distinction did not exist at that time. As the research areas of (poly)peptoids obtained via stepwise solid-phase submonomer synthesis (SPSS) and of those obtained by nucleophilic living condensative ring-opening polymerization (NuLCROP) have started to overlap in recent years, the terminology is sometimes a bit unclear. Against recommendations by IUPAC, the terms polydisperse and monodisperse remain common in the literature. Especially in the context of peptoids, these terms are particularly misleading. Therefore, we will use the term uniform for peptoids obtained from SPSS, as they are usually sequence and chain-length specific (disregarding impurities). The term nonuniform will be used in this Review for products obtained by NuLCROP, as they will always comprise a distribution of molar masses and cannot be sequence specific. Moreover, we will use the term peptoid for sequence-specific products of the submonomer synthesis, while polypeptoid will be used for the products of the ring-opening poylmerization. If unspecified, we will use the term (poly)peptoids. Higher homologues such as polymers of N-substituted β-alanine will be termed poly(β-peptoid)s, poly(γ-peptoid)s, and so on. With respect to the structure of (poly)peptoids, the primary structure is, as defined for peptides, the sequence of the repeating units. The secondary structure describes the relative short-range orientation of the repeating units, such as helices, sheets, loops, and turns. These secondary structures may organize to larger structural units, the tertiary structure. This structural hierarchy is defined intramolecularly. Herein, we will denote any structural motif, which involves intermolecular assembly as a quaternary (i.e., supramolecular) structural motif. Thus, micelles, supramolecular helices, and sheets, usually assembled from large numbers of individual (poly)peptoids fall into this category. In this definition, we deviate somewhat from the definition of quaternary structure in protein science, as structures of polymer micelles and sheets are much less defined as for example hemoglobin or even complex natural assemblies such as viral capsids. In this Review, we aim to provide a comprehensive overview over peptoids and polypeptoids, their history, synthesis, physicochemical characteristics, as well as reported and potential applications. While advancing the frontier of supramolecular and macromolecular engineering with (poly)peptoids, we also need to be aware of what has been done before. We would like to note that in recent years, several other reviews on (poly)peptoids were published,32−34 some of which were focused on particular aspects,35 such as synthetic aspects of polypeptoids,36 hierarchical structures,37 or applications for sequence-specific peptoids.38 Other reviews are rather comprehensive.39 We would like to highlight in particular a recent Commentary by Zuckermann, a pioneer of peptoid

research.40 Here, we attempted to look both deeper and further than what we believe has been done before. We are also discussing a number of papers which appear to have been forgotten for decades. On the one hand, this should prevent reinventing the wheel with respect to (poly)peptoids in the years to come, and on the other hand, we hope that this gives a more complete picture from which we can develop this family of materials further in the future. At the same time, we intend to present a complete picture of why we believe that (poly)peptoids stand at the moment at the frontier of supramolecular and macromolecular engineering.

2. SYNTHESIS AND CHARACTERIZATION OF (POLY)PEPTOIDS (Poly)peptoids are characterized by their high versatility in molecular design and promising properties. Depending on the desired chain length, quantity, and degree of definition (uniform or nonuniform), two different approaches toward the synthesis of (poly)peptoids have been investigated intensively. On the one hand, ring-opening polymerization of NNCAs is a facile and rapid method to obtain disperse polypeptoid chains up to high degrees of polymerization with excellent definition. On the other hand, stepwise solid-phase submonomer synthesis provides an opportunity to obtain essentially uniform peptoids. 2.1. Ring-Opening Polymerization

Ring opening polymerization (ROP) of heterocyclic NNCAs is a facile and convenient and frequently used strategy for making well-defined polypeptoids and can be performed either in solution, in bulk, or on solid phase. In principle, the NNCAs bear two reactive centers, the electrophilic the electrophilic C2 and C5 opening of the heterocycle can be achieved by different types of initiators. Most commonly, nucleophiles are used, with primary amines being the most intensively investigated species. Polymerization proceeds following the so-called normal amine mechanism (Scheme 2), which was proposed for sarcosine-NCA by Waley and Watson41 in the middle of the 20th century. Nucleophilic attack of the initiator on C5 induces ring opening and formation of a carbamic acid. After elimination of carbon dioxide, a secondary amine becomes available for further propagation. Overall, ROP of NNCAs has a highly living character but is very sensitive to nucleophilic impurities. However, it should be noted that such impurities will not lead to termination of the polymerization but rather to unwanted initiation and potentially multimodal products. The controlled manner of this method was demonstrated with NNCAs bearing different alkyl side chains (R = methyl, ethyl, propyl, n-butyl, iso-butyl), yielding polymers with Poisson distribution and degrees of polymerization in good agreement with the monomer-toinitiator ratio ([M]0/[I]0), if the chain length is short or moderate. At higher degrees of polymerization, many researchers have observed that the chain lengths are often 1755


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multiblock copolypeptoids bearing aliphatic side chains (C1− C5) were performed by the Luxenhofer group,44,54 thus pointing out the extraordinarily robust living character of the NuLCROP of NNCAs (Figure 3). Strong dependence of the

lower than expected.42−45 This, however, seems not to be a systematic or method related error and is likely to be attributed to impurities in the reaction mixture. The living character of the polymerization was first demonstrated by Waley and Watson.41 The Poisson-type distribution of the products was first demonstrated by Sisido et al.46 2.1.1. Side Chain Variations. For many decades, methyl was the predominant substituent employed. Higher homologues were barely investigated and polymer properties remained essentially unknown. Much longer aliphatic side chains up to C14 were later introduced by Zhang et al.47 Early work suggested that other N-substituted NNCAs are not suited for polymerizations. For example, N-iso-propylglycine-NCA was thought to be not polymerizable using NuLCROP after early reports.48 However, Schlaad and co-workers obtained poly(N-iso-propylglycine) with low dispersity in bulk polymerization by addition of the initiator directly to a melt of the NNCA.49 After many decades, in which virtually the only polypeptoid was PSR, the molecular toolbox for NNCA monomers has increased to more than a dozen (Figure 2).

Figure 3. Kinetic investigations of the ring-opening polymerization of N-substituted N-carboxyanhydrides. (a) Sarcosince-NCA polymerizes faster than N-ethylglycine, but no conclusive trend was observed with respect to the influence of pressure on the polymerization rate. (b) Addition of strong Brønsted acids (trifluoromethane sulfonic acid, TMSA) can be used to adjust the polymerization rate while the polymerization retains a living character. (c) A profound influence of the polymerization rate of NNCAs was found. For example, Sar-NCA polymerization in benzonitrile was found much faster than in Nmethylpyrrolidone (NMR). However, the polymerization of Sar-NCA is faster in NMP than the polymerization of N-n-butylglycine-NCA. Reprinted from ref 43. Copyright 2011 American Chemical Society.

Figure 2. Overview of N-substituted glycine N-carboxyanhydrides that have been used for ring-opening polymerization to date.43,45,47,49,50

The incorporation of substituents bearing functional groups instead of simple alkyl side chains requires additional protection of the functional groups if these would interfere with monomer or polymer synthesis. Nevertheless, variability of functional side chains is essential for the development of (poly)peptoids as smart or functional biomaterials. Therefore, post-polymerization modifications currently represent the method of choice. Schlaad and co-workers described the synthesis and polymerization of N-allylglycine-NCA for further modification, for instance with sugar, using thiol−ene photochemistry.51 Zhang and co-workers applied copper catalyzed [3 + 2] azide− alkyne cycloaddition click chemistry to copolypeptoids with Npropargyl side chains.52 More recently, Schlaad et al. demonstrated the great potential of poly(N-propargylglycine) as a platform for modification of polypeptoids53 (see section 2.4.3). 2.1.2. Polymerization Kinetics. More detailed investigations on the synthesis and characterization of both homo and

polymerization rates on the substituents (methyl ≫ ethyl > propyl > n-butyl > iso-butyl) as well as on the reaction medium (benzonitrile > N-methyl-2-pyrrolidone > tetrahydrofuran) was observed during kinetic studies. All polymerizations proceeded to quantitative monomer conversion following pseudo firstorder kinetics, the molar mass of the polypeptoid was linearly proportional to monomer consumption, and polymers exhibited Poisson distribution. Furthermore, kinetic investigations on the influence of substoichiometric amounts of a strong acid (trifluoromethanesulfonic acid, TMSA) revealed lowering of the propagation rate. In contrary, substoichiometric amounts of weak acids were reported to increase the propagation rate.55 In order to assess influences of the CO2 partial pressure and reaction temperature in detail, further kinetic studies are required. In the case of NHC-catalyzed ROP 1756


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Scheme 3. Different Approaches Toward (Poly)(β-peptoid)s that Have Been Described in Literaturea

a

Reprinted with permission from ref 39. Copyright 2013 Wiley Periodicals Inc.

ethylglycine and N-butylglycine was published by Zhang and co-workers. In order to prove the random character of the copolymerization, reactivity ratios of both monomers were measured and determined according to the Fineman−Ross method and found to be nearly identical.71 More recently, similar copolymers were employed as macroinitiators for polymer brushes (see section 2.4.2.1).72 Random copolymers obtained from sarcosine and butylglycine N-thiocarboxyanhydrides (sarcosine- and BuGly-NTA) were shown to be thermoresponsive and exhibit reversible phase transitions in aqueous solution.69 2.1.4.2. Block Copolymers. Taking advantage of the ROP living character, Guo and Zhang were first to report the synthesis of block copolypeptoids.73 Their work was mainly focused on the investigation of cyclic polypeptoids (see section 2.4.1), linear block copolypeptoids comprising N-methylglycine (sarcosine), and N-butylglycine were synthesized for the purpose of comparison. However, the characterization of these linear polymers was limited to 1H NMR spectroscopy and viscometry, therefore, one could argue that the block copolymer character was not demonstrated at this time. Since then, the possibility of preparing multiblock copolymers either by consecutively adding fresh monomer directly to a polymerization reaction or by the use of macroinitiators has been demonstrated.43−45,74 2.1.5. (Poly)(β-peptoid)s and (Poly)(γ-peptoid)s. The polymer class of (poly)(β-peptoid)s can formally be obtained by the addition of a single methylene group to the backbone of an (poly)peptoid or the N-substitution of (poly)(β-peptide)s. Although a larger number of synthetic routes can be applied in order to synthesize (poly)(β-peptoid)s (Scheme 3), both monomer and polymer synthesis are more challenging as compared to polypeptoids. Furthermore, poor solubility in most common solvents impedes handling and applicability in drug delivery.75 Like polypeptoids, poly(β-peptoid)s can be obtained by ROP of the respective NNCAs, which are, in case of the poly(βpeptoid)s, six-membered rings instead of a five-membered ones. Around 1960, a couple of different β-NCAs and β-NNCAs have

of NNCAs in toluene and DMSO, excess pressure of CO2 did not appear to have any influence, as reported by Zhang.56 Also an earlier paper57 and a very recent DFT calculation by Liu and Ling58 suggest that the decarboxylation is not the ratedetermining step. 2.1.3. Polymerization of N-Thiocarboxyanhydrides. NNCAs are known to be highly susceptible to hydrolysis; this fact may have hampered development of the field for decades. Therefore, a number of attempts toward polypeptides and polypeptoids from the more stable (N-substituted) Nthiocarboxyanhydrides (NTAs) have been made. First synthesized in the 1950s,59−61 NTAs are known to be less sensitive to moisture and heat, thus providing higher long-term stability. NTAs have been applied for the stepwise synthesis of oligopeptides62−64 but also in polymerizations.65−67 Primary amine-initiated polymerizations of sarcosine-NTA as well as D,L-leucine-NTA and D,L-phenylalanine-NTA were investigated by Kricheldorf et al. in 2008.68 Although both yield and degree of polymerization of the polymers obtained from sarcosineNTA were almost twice as high as compared to polymers obtained from D,L-leucine-NTA and D,L-phenylalanine-NTA, the molar masses remained unpredictable, and NTAs were thought to be unsuitable for the preparation of high molar mass polymers. In 2014, Ling and co-workers demonstrated the convenient and controlled ROP of sarcosine-NTA initiated by amineendfunctionalized poly(ethylene glycol) (PEG).69 In contrast to Kricheldorf, who performed polymerizations at room temperature, Ling et al. applied a reaction temperature of 60 °C, yielding well-defined block copolymers and degrees of polymerization in good agreement with the feed ratios of monomer to initiator. The same group was the first to synthesize, characterize, and polymerize N-butylglycine-NTA.70 Using rare earth borohydride initiators, polymerization proceeded largely controlled up to a monomer-to-initiator ratio of 300. 2.1.4. Copolymerization of N-Carboxyanhydrides. 2.1.4.1. Random Copolymers. A detailed characterization of thermoresponsive random copolypeptoids consisting of N1757


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Scheme 4. Peptoid Synthesis by Monomer and Submonomer Methoda

a

For each type, one monomer addition is represented. Every approach can be divided in acylation and amination, which can be repeated several times followed by a final cleavage step.

solid-phase synthesis which was pioneered by Merrifield for peptides.88 Today, solid-phase organic synthesis is a widely applied concept that is used commercially and in academia. It is employed worldwide to create sequence-specific oligomers or small polymers such as oligosaccharides or oligonucleotides which underlines the continued and outstanding importance of this method. Besides the advantages, the highly inefficient synthesis and the restricted chain length, usually less than 50 monomer units, have to be considered. Throughout the literature, we could identify five methods for the stepwise synthesis of peptoids (Scheme 4). Early approaches toward solid-phase synthesis of peptoids by Simon et al., subsequently termed monomer method, are essentially analogous to 9-fluorenylmethyloxycarbonyl solidphase peptide synthesis (Fmoc SPPS) (Scheme 4A), however, with the main difference that N-substituted glycine monomers are used instead of regular amino acids. A major disadvantage of this approach is the necessity to prepare protected Nsubstituted glycine monomers, which are not readily available and not always easy to synthesize.89 As Scheme 4 indicates, the other four methods (collectively referred to as submonomer methods) have in common that the acyl and amine functions of each monomer unit derive from two different steps. Route B, strongly related to the monomer method, is based on the reductive alkylation of glycine with the suitable aldehyde or ketone to obtain the desired N-alkylated glycine derivative (Scheme 4B).90,91 The most common submonomer method, often termed solid-phase submonomer synthesis (SPSS), was developed by Zuckermann and co-workers by using two readily available building blocks, so-called “submonomers”.92 In a first step, a haloacetic acid, activated in situ with N,N′-diisopropylcarbodii-

been investigated for polymerization. Initially, Birkofer et al. demonstrated the successful synthesis and subsequent polymerization of N-p-tolyl-β-alanine-NCA by both thermal and nucleophilic initiation using p-toluidine.76 Furthermore, Nphenyl-β-alanine-NCA was polymerized by heating above the melting point as well as nucleophilic initiation by water.77 Zilkha and co-workers reported the synthesis of poly(N-benzylβ-alanine) from ROP of N-benzyl-β-alanine-NCA, whereas Nbenzyl-β-aminobutyric acid-NCA as well as N-benzyl-β-aminoisobutyric acid-NCA showed no tendency to polymerize.78 A long time later, Luxenhofer et al. demonstrated the living character of N-substituted β-alanine-NCA polymerization.79 Kinetic studies revealed pseudo-first-order kinetics with high fidelity of the propagating species up to high monomer conversions. As shown by MALDI-TOF-MS measurements, homo as well as block copolymers with Poisson distribution were obtained. However, solubility was a major issue, and the polymers had a strong tendency to precipitate from the reaction mixture. Apart from ROP of NNCAs, β- as well as poly(γ-peptoids) can be obtained using a metal-mediated ROP approach. In this case, N-alkylaziridines80,81 or N-alkylazetidines,82,83 respectively, are copolymerized with carbon monoxide in a so-called metal-catalyzed carbonylative polymerization of heterocycles (COPH), which also has been employed in the synthesis of polyesters84,85 and polyamides.86,87 2.2. Solid-Phase Syntheses toward Highly Defined (Poly)peptoids

2.2.1. Stepwise Synthesis from Solid Supports. Chemical synthesis of polymers with absolute sequence control and control over the chain length is only possible by using 1758


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Scheme 5. Illustration of (Poly)peptide and (Poly)peptoid Syntheses Using Solid Supportsa

a

While the solid-phase submonomer synthesis has been developed over the last 20 years, the stepwise synthesis of oligopeptides has been pioneered by Merrifield, which won him the Nobel Prize in Chemistry in 1984. In contrast, the ring-opening polymerization of NCAs and NNCAs using solid supports has been developed recently. Reprinted with permission from ref 39. Copyright 2013 Wiley Periodicals Inc.

on stable helical structures designed by β-peptoids hexamers will be discussed in section 3.2.2. 2.2.2. Ring-Opening Polymerization from Solid Supports. The advantages of the solid-phase synthesis appear promising also for polymer-analogue modifications and, thus, macromolecular engineering. To drive polymer modification to high yield, the use of a large excess of reactant, with which the polymer should be modified, is highly beneficial. For the preparation of bioconjugates, the possibility to use a gel, which is preloaded for example with a peptide sequence,99 is intriguing. Consequently, the combination of SPPS and solid-phase initiated polymerization has been studied by several researchers.99,100 Recently, Luxenhofer and co-workers have reported on the solid-phase peptoid polymerization (SP3) using Rinktype resins as initiators and N-substituted glycine-NCAs as monomers.74 It was found that numerous parameters are relevant to achieve well-defined polymers without excessive fractionation employed before.99 Besides the amine density on the resin, which should be rather low, the monomer concentration should be relatively high (1M). Furthermore, in order to slow down the polymerization rate with respect to monomer diffusion into the gel, addition of acids for partial protonation of the propagating species has been demonstrated to be advantageous for achieving low polymer dispersity. Furthermore, the authors demonstrated that the polymerization has a living character to essentially quantitative monomer conversion. On the basis of these results, the authors prepared a pentablock copolymer, similarly as has been shown before for synthetic approaches in solution.44 The pentablock copolymer was well-defined as has been shown by gel permeation chromatography (GPC). Besides the fact that this new approach is very interesting for bioconjugates and polymer therapeutics, it also can be freely combined with SPPS or SPSS, which is very intriguing for the preparation of complex macromolecular structures (Scheme 5). 2.2.3. Combinatorial Libraries for Peptoid Ligand Screening. The efficient discovery of drugs or biomolecular ligands almost appears inconceivable today without the usage of

mide (DIC), is attached to the resin followed by SN2 substitution of the halogen with a primary amine. The decisive advantage of this strategy lies in the use of primary amines to introduce the substituent. Besides the fact that these are available in a large variety, they are also often rather inexpensive compared to protected amino acids or protected N-substituted amino acids. Nevertheless, side chains with reactive functional groups require protection, even though many heterocycles can be used directly without protection.93 Using SPSS, uniformity with respect to chain length and monomer sequence is possible, in theory. In reality, purities of ≥95% (after purification) are regularly reported for peptoids with up to 50 monomer units. Recently, the use of N-substituted o-nitrobenzenesulfonamide derivatives as alternative building blocks in the synthesis of peptoids was demonstrated by Biron and co-workers (Scheme 4D).94 This approach is suitable for the preparation of peptoids bearing different hydroxylated side chains. Kodadek and co-workers adapted the submonomer method for the photolithographic synthesis of arrays by implementing a light dependent process into the synthetic scheme (Scheme 4E).95 Usage of UV-irradiation to unmask a protected surface moiety allows for the creation of spatially defined arrays. Furthermore, sequence-defined β-peptoids are accessible via SPSS. Hamper and co-workers applied a two-step approach by using a Wang resin as solid-phase and acrylic acid and primary amines as submonomers.96 In a first step, acryloyl chloride was linked to the resin, followed by the Michael addition of the appropriate amine. Hamper et al. prepared several different βpeptoids. However, they comprised only two or three monomer units. Shuey and co-workers reported solubility issues with β-peptoids after they reached approximately five repeating units, a major issue also in the polymerization of βNNCAs (see section 2.1.5). To overcome these limitations, Shuey et al. coupled oligomers comprising three or four repeating units in solution to obtain longer chains up to 18 units.97 In 2006, Arvidsson et al. described the solid-phase synthesis of N-chiral β-peptoids with phenylethylamine substituents.98 Due to several optimizations, the chain length could be extended up to 11 monomer units. Very recent results 1759


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Scheme 6. Proposed Mechanism of NHC-Mediated Polymerization of NNCA73a

a

Due to coulomb interactions, chain ends of the zwitterionic intermediate species remain in close contact. Adapted from ref 56. Copyright 2012 American Chemical Society.

combinatorial library synthesis that provides an efficient way to achieve high molecular diversity. Thus, a variety of approaches for spatially resolved immobilization of peptoids has been researched. Although this issue may appear rather remote from our common approaches of supra- and macromolecular engineering, we believe that the synthetic possibilities available for (poly)peptoids are ideally suited to look beyond the common approaches. At first, it was obvious to adapt techniques like the SPOT synthesis, which was first presented by Frank and is well-established for the rapid preparation of peptide arrays.101,102 Wenschuh and co-workers performed solid-phase synthesis on cellulose membranes using an adjusted submonomer approach.103 Due to the different kinetic situation on continuous surfaces and the large number of free hydroxyl moieties on the cellulose, bromoacetic acid 2,4-dinitrophenylester was used for the acylation of the secondary amine of the growing peptoid. Since every single reaction is spatially isolated from its neighbor, a library consisting of thousands of peptoids is obtained on the solid support. Another common method is the usage of peptoid-based small-molecule microarrays (SMMs) that provide unique patterns for individual proteins, demonstrating the ability of peptoid libraries for biological applications.104 Kodadek et al. produced these arrays by first synthesizing a peptoid library on 500 μm poly(styrene) resins using split and pool synthesis. To prepare microarrays consisting of more than 7.500 octameric peptoids, they attached the synthesized oligomers to maleimide-functionalized glass microscope slides. Either fluorescein-labeled proteins or unlabeled proteins visualized with a fluorescent secondary antibody were hybridized to those arrays resulting in identification of reproducible and unique patterns. On the basis of these experiments with purified proteins, Kodadek and co-workers investigated the suitability of the peptoid microarrays employing an antibody-based sandwich assay. More particularly, they hybridized a mixture of native proteins to the arrays then probed it with an antibody raised against a certain target protein. To complete the sandwich structure, the array was labeled with a secondary antibody. The sensitivity limit is between 10 and 100 nM of protein and is

thus well below the binding affinities earlier identified for peptoid-protein interactions. Moreover, the Kodadek lab evolved a general method to identify diagnostically useful antibodies without the demand for antigen identification, by using combinatorial peptoid arrays. They discovered potentially suitable diagnostic biomarkers in humans via identification of two candidate IgG biomarkers for Alzheimer’s disease.105 Also using small molecule microarrays, Disney and co-workers identified peptoids that inhibit the group I intron RNA from Candida albicans, an opportunistic pathogen that is problematic for immunocompromised hosts.106 Furthermore, Kodadek and co-workers synthesized arrays of different cyclic peptoids by using an optimized “one bead two compound” approach that is tailored to the creation of microarrays.107 Formats like equimolar mixture screening,108,109 OBOC (one-bead-one-compound) screening110,111 and positional scanning libraries112,113 also contribute to the variety of available combinatorial libraries. By using the first method, Zuckermann and co-workers at the Chiron Group discovered several effective peptoid trimer ligands for G-protein-coupled receptors.108 2.3. Ribosomal Synthesis

A relatively novel approach toward the synthesis of (poly)peptoids and peptoid-peptide hybrids, which is referred to as ribosomal synthesis, was introduced by Suga et al.114 Directed by mRNA, this method is based on the translation machinery, using genetic code reprogramming. For this, two different systems are applied: artificial tRNA translation ribozymes (flexizymes) and wPURE, a reconstituted E. coli cell-free system in which proteinogenic amino acids or related aminoacyl-tRNA synthetases are withdrawn. Ribosomal synthesis was shown to be not suited for bulky or charged substituents. However, the same group recently demonstrated the introduction of charged functional groups by post-translational bio-orthogonal chemical or enzymatic conversion.115 Although, peptoid-peptide hybrids were prepared successfully, linear (poly)peptoids could not be obtained so far. 1760


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Figure 4. Comparison of the (a) 1H NMR (60 MHz) of cyclotrisarcosyl (in CDCl3) and (b) cyclohexasarcosyl (in CD3OD). Reprinted with permission from ref 126. Copyright 1969 Royal Society of Chemistry. (c) Spatial view of the energetically favored “crown” conformation of cyclotrisarcosyl. Atoms are color-coded (gray, carbon; white, hydrogen; red, oxygen; blue, nitrogen). Remodelled with ChemBio3D Ultra 13.0 using data from ref 128.

2.4. Macromolecular Engineering

Inspired by these results, Zhang and co-workers investigated the NHC-mediated ROP of NNCAs.73 Well-defined cyclic diblock copolymers of N-butylglycine-NCA and sarcosine-NCA were obtained by sequential addition of the monomers. Further studies revealed that polymer weight as well as propagation rate are dependent on and controllable by the choice of the NHC as well as the solvent.56 In solvents like tetrahydrofuran (THF) and toluene, which have low dielectric constants, characteristics of a living polymerization are observable. Suppression of side reactions is based on the reduced nucleophilicity and basicity of negatively charged chain ends of the zwitterionic propagating species. Both chain ends remain in close contact due to Coulombic interactions, thus maintaining a cyclic architecture during polymerization (Scheme 6). In contrary, polymerizations in solvents with high dielectric constants, such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), are strongly influenced by side reactions. More detailed investigations on the NHC-mediated ROP of N-butylglycine-NCA revealed that the degree of

2.4.1. Cyclic (Poly)peptoids. Kricheldorf et al. observed the formation of substantial proportions of cyclic PSR after initiation of sarcosine-NCA polymerization with pyridine.67 However, due to simultaneous formation of linear PSR, control over the molecular weight of the resulting polymer is very limited. Further formation of significant amounts of cyclic PSR were described by initiation using tertiary amines like Hünig’s base, N,N-diisopropylethylamine,116 and thermal polymerization in bulk at 120 °C117 or solvent-induced nucleophilic polymerization.118 In all cases, polymerization was assumed to proceed via a zwitterionic mechanism. N-Heterocyclic carbenes (NHCs) are well-known as a class of catalysts for the ROP of various heterocyclic monomers including cyclic esters,119 carbonates,120 siloxanes,121 and oxiranes like ethylene oxide,122,123 yielding polymers with defined molar mass and low dispersity. 1761


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polymerization is well-adjustable by the initial ratio of monomer to NHC.56 Kinetic studies in toluene demonstrated similar effects of the substituents on the propagation rate as observed for linear polymerizations (ethyl > propyl = n-butyl > allyl). Furthermore, an inverse relationship between propagation rate and steric demand of the NHC was observed; polymerization proceeds faster with less sterically demanding NHCs. However, it should also be noted that in many cases GPC traces often show a shoulder or bimodality at higher molar masses. This could point toward chain coupling events during the reaction, which are easily envisioned in the zwitterionic mechanism. However, artifacts from GPC analysis cannot be excluded. Besides these comparably large cyclic polypeptoids, a few groups have also worked on the cyclization of peptoids. Here, we want to mention two interesting papers that highlight and review this topic in a more detailed manner.124,125 Interestingly, it appears that also in this instance, peptoids, in particular oligo(sarcosine) were initially investigated as a easier-to-handle alternative to oligopeptides several decades ago.126,127 The NMR studies on cyclic oligo(sarcosine)s by Titlestad and coworkers are very interesting and a showcase for the structural effects on the 1H NMR spectra of oligo- and poly(sarcosine)s. Exemplarily, while the cyclic trimer exhibits a single signal for the methyl group, the methylene group splits into a quartett with an extremely large coupling constant (Figure 4a). Such spectrum can be explained by a single configuration of all amide groups (cis) and a ring structure that deviates strongly from planar. The energetic preference for such cis−cis−cis “crown” structure was recently confirmed by DFT calculations (Figure 4c).128 In contrast, the 1H NMR spectrum of a cylic hexamer shows no hint toward any structural preference (Figure 4b). In fact, this NMR spectrum essentially looks like the spectrum of a linear poly(sarcosine). Unfortunately, the authors measured the hexamer in deuterated methanol, while all other spectra were obtained in CDCl3 and the solvent has a major influence on the structural preferences of (poly)peptoids.45,129 The cyclic oligomers were obtained after activation of the C-terminus as 2,4,5-trichlorophenylester in pyridine at high dilution (i.e., a head-to-tail approach). Purification was achieved by ionexchange chromatography and subsequent sublimation. Titlestad et al. later reported on a crystal structure of cyclooctasarcosyl.127 Later, Kirshenbaum et al. also used a head-to-tail approach to form macrocycles of a sequence synthesized via the stepwise solid-phase submonomer synthesis (Figure 5a).130 They synthesized a broad array of sequences from five to 20 repeat units and cyclized them within 5 min at room temperature. As previously observed by Titlestad,126,127 the macrocyclization leads into an enhanced conformational ordering due to the covalent constraint and made the crystallization of cyclic peptoid hexamer and octamer possible. These first X-ray crystallographic structures of peptoid hetero-oligomers suggest that peptoid macrocycles can assemble into a reverse-turn conformation, which will be discussed in section 3.2.3. Apart from the described head-to-tail formation of peptoid macrocycles by amide coupling chemistry,130−132 side-chain-to-tail formation via boronate esters133 have been utilized as well. Another approach is to form macrocycles directly on the solid support before cleaving the peptoid structures. Here, sidechain-to-side-chain cyclization via cycloaddition (Figure 5b)134 and side-chain-to-tail cyclization via ring-closing metathesis (Figure 5c),135 amide coupling,136 nucleophilic substitution

Figure 5. Chemical structures of (a) head-to-tail cyclized peptoid hexamer by amide coupling after cleavage from the solid support, (b) side chain-to-side chain cyclized peptoid octamer by [3 + 2] azide− alkyne cycloaddition and (c) side chain-to-tail cyclized peptoids by ring-closing metathesis. The latter are cyclized while still linked to the solid support and subsequently cleaved from it. Reprinted with permission from refs 130, 134 and 135. Copyright 2007 and 2011 American Chemical Society.

under microwave irradiation,137 thioether formation138 or triazine bridges (Scheme 7)139 have been used. The latter two approaches are especially intriguing strategies for post highthroughput screening conversion via ring-opening into linear peptoids, which can be sequenced by tandem mass spectrometry. Another approach to synthesize and cyclize peptoid oligomers is via head-to-tail formation without a solid support directly in solution.140,141 By this route, also cyclic βpeptoids,142 α,β−peptoids,143 and semipeptoids144 could be synthesized. Finally, to enhance the conformational ordering even more by an additional covalent constraint, side chains of macrocycles have been bridged to form bicyclic peptoid structures, either directly on the solid support (Scheme 8),145 or in solution.146 Considering these constrained structures and their relatively large size, one might think of those bicyclic peptoids as promising modulators of protein−protein interactions or as scaffolds for drug design. 2.4.2. Branched Polypeptoids and Polypeptoid Brushes. Multi- and macroinitiators as well as macromonomers enable the generation of polymers with versatile appearance strongly depending on the nature of the initiator or the macromonomer. Branched and hyperbranched polymers as well as polymer brushes are an important aspect of macromolecular engineering. As initiators for the NuLCROP, primary amine groups are particularly well-suited. These functional groups can be attached to surfaces like glass or they are terminal groups of other polymers/side chains like a poly(trimethylenimine) dendrimer, chitosan, or a linear poly(N-(6aminohexyl)methacrylamide).147−153 2.4.2.1. Polymer Brushes. Polymer brushes can be synthesized in solution72,154−158 or on surfaces.159−162 The first approach gives products resembling molecular bottlebrushes, while the second one gives structures resembling carpet-like structures.72,150−153 Also carpets of bottlebrushes can be produced.163−165 1762


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Scheme 7. Representation of the Encoding-Free Strategy to Convert a “Hit” Cyclic Peptoid into a Sequenceable (By Tandem Mass Spectrometry) Linear Peptoida

a

After oxidation of the thioether, the sulfone acts as a leaving group and can be released by a nucleophilic displacement reaction. Reprinted with permission from ref 139. Copyright 2010 The Royal Society of Chemistry.

the result by Frank et al. obtained for surface-initiated vapor deposition polymerization (SI-VDP).170 Hydrophilic, hydrophobic, and amphiphilic polypeptoid brushes could be obtained in a straightforward manner. The amine-modified surfaces only need to be immersed in a monomer solution. Furthermore, the formation of block copolymer brushes was demonstrated. Again, this could easily be achieved by immersing the polypeptoid-modified surface into a fresh monomer solution (Figure 6a). Water contact angle measurements not only indicate the living character of SI-ROP of NNCAs but also hint at a dense nature of the obtained brushes. Restructuring of the polymer brushes, when a hydrophilic brush was topped by a hydrophobic brush and subsequently incubated with water could not be detected.150 More recently, the same group demonstrated that structured polypeptoid brushes are accessible either via photolithographic route or via microcontact printing (Figure 6b).151 2.4.2.1.2. Graft Copolymers and Brushes from Multifunctional Initiators. Another class of intriguing molecular architectures, featuring a linear polymeric backbone and densely grafted side chains, are bottlebrushes.171 Aoi and coworkers used grafting from macroinitiators with multiple initiation sites, namely chitin and chitosan, for ROP of sarcosine-NCA in DMSO.148,149 Unfortunately chitin, which can be degraded by enzymes like Chitinase or lysozyme, is poorly soluble and hence is less used as material. Graft copolymers having longer side chains exhibited higher solubility in water. Additionally, the authors were able to demonstrate that chitin-graf t-poly(sarcosine) is still degraded by the aforementioned enzymes.148 Subsequently, chitosan, an amino polysaccharide obtained by alkaline deacetylation of chitin, was used as macroinitiator.149 However, chitosan is, like chitin, poorly soluble in common organic solvents. The synthesis of chitosan-graf t-poly(sarcosine) in DMSO is controlled through the use of carboxylic acids like nicotinic acid or isonicotinic acid. The propagating amine is in equilibrium with a dormant ammonium species and, however, the equilibrium being shifted to the ammonium side. A similar mechanism has been described by Schlaad et al. for the ammonium-mediated ROP of NCAs.172,173 Recently, Zhang and co-workers used a different approach, namely a grafting-through approach. They copolymerized Nethylglycine- and N-butylglycine-NCAs using a 5-norbornene2-methylamine initiator. Afterwards, they polymerized the polypeptoid macromonomer by ring-opening metathesis polymerization (ROMP) using the Grubbs’ second generation

Scheme 8. Synthetic Strategy of a One-Step Bicyclization into a Triazine-Bridged Bicyclic Peptoida

a

Reprinted from ref 145. Copyright 2011 American Chemical Society.

2.4.2.1.1. Brushes by Surface-Initiated Polymerization. It is typically argued that polymer brushes with high density are only accessible by a grafting-from approach.161 Therefore, the surface-initiated (SI) polymerization is crucial. These processes have been studied for polypeptides for some time. Initially, this was realized by SI-ROP of NCAs by immersing the aminofunctionalized surface in a suitable monomer solution.166 However, the average thickness is only 0.11 nm as determined by ellipsometry. Klok and co-workers used Nε-oligo(ethylene glycol)succinate-L-lysine-NCA as a monomer and two different aminosilanes immobilized on silicon, glass, or quartz substrates as initiators. The achieved thickness was below 5 nm. Nevertheless, the brushes were reported to be effective in avoiding nonspecific protein adsorption.167 Besides the described approaches in solution, Frank and co-workers have studied the chemical vapor polymerization of NCAs to obtain polypeptide brushes using amine-functionalized surfaces.168−170 Since polypeptoids are intriguing alternatives to polypeptides, Jordan, Luxenhofer, and co-workers investigated the SI-ROP of NNCAs from solutions using (3-aminopropyl)triethoxysilane (APTES) modified silicon dioxide substrates as initiators.150 Surprisingly, the brush height that could be realized resembles 1763


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Figure 6. (a) Preparation of amphiphilic block copolypeptoid brushes from amine-functionalized surfaces by living surface initiated ROP via consecutive monomer addition. Sarcosine-NCA yields hydrophilic brushes (blue) while N-butylglycine yields hydrophobic ones (red). Reprinted from ref 150. Copyright 2013 American Chemical Society. (b) Patterned SAM initiator surfaces by microcontact printing (top) and UV-lithography (below) and consecutive surface-initiated living condensative ring-opening polymerization (SI-LCROP) of sarcosine-NCA to patterned PSR brushes. The brush terminal secondary amine was further used for selective functionalization with different dyes as model compounds. Reproduced with permission from ref 151. Copyright 2015 Wiley-VCH.

Scheme 9. Synthesis of Cylindrical PSR Brushesa

catalyst.72 Thus, by choosing appropriate monomers, amphiphilic bottlebrush copolypeptoids could be obtained. More recently, Hörtz et al. investigated cylindrical brushes with polypeptoid side chains.152,153 In contrast to Zhang et al.,52 they used multimacroinitiators, namely poly(N-(6aminohexyl)methacrylamide) (PAHMA) and poly(L-lysine) (PLL), to polymerize sarcosine-NCA or to generate core− shell brushes, consisting of sarcosine and lysine, in a graftingfrom approach (Scheme 9). PSR brushes were also functionalized with azide groups on the ends of their side chains, which can be utilized for further bioconjugation.52 2.4.2.2. Star Polymers. In a wide range of fields from molecular science to materials science, spherical molecules and structures are of growing interest because of their significant features. For example, star polymers exhibit a low viscosity and are discussed as unimolecular micelles (e.g., for drug delivery). Especially the synthesis of dendrimers and linear polymers as block copolymers is intriguing due to the combination of characteristic properties.174,175 Very recently, Adeli et al. summarized the importance of linear−dendritic copolymers as supramolecular anticancer drug delivery systems.176 Okada and co-workers used poly(trimethylenimine) (PTMI) dendrimer of 64-NH2-terminal-type to initiate the ROP of sarcosine-NCA (Figure 7).147 The authors postulate that initiation from all the terminal amino functions occurred even for the shortest chain length, consisting of only two monomer units. They refer to the 13C NMR spectra that do not show attributed to α- and β-

a

AFM height micrographs of (a) PSR brush spin-cast from methanolic solution (backbone: polymethacrylate; spacer: 6-aminohexyl; counterion: TFA) and (b) PSR brush spin-cast from aqueous solution (backbone: polypeptide; spacer: 4-aminobutyl; counterion: HBr). Adapted from ref 153. Copyright 2015 American Chemical Society.

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Figure 7. When using a poly(trimethyleneimine) initiator for the radial-growth polymerization of sarcosine-NCA, star-like PSR is obtained.147

methylene moieties of unreacted termini of the PTMI. We find it important to note that this is rather unlikely based on purely statistical consideration: taking into account a Poisson distribution function, the probability for unreacted amine functions should be about 14% (about 9 out of 64). It is questionable whether a cursory analysis by 13C NMR spectra is suitable to rule out the presence of unreacted dendrimer termini at this relation. However, this discrepancy might be explained by a significantly faster initiation as compared to propagation. Since it may be considered a reasonable assumption that primary amines react faster as compared to the propagating species. However, to the best of our knowledge, this has not been experimentally confirmed or quantified in this context. 2.4.3. Polymer-Analogue Modification of (Poly)peptoids. Schlaad and co-workers described the synthesis and polymerization of N-allylglycine-NCA for further modification using thiol−ene photochemistry.51 In absence of a photoinitiator, irradiation with UV-light yielded moderate degrees of modification as determined by ESI mass spectrometry as well as 1H NMR spectroscopy. Short poly(N-allylglycine)s, having less than 20 repeat units and being soluble in water, could be reacted with 1-thioglycerol or 1-thio-glucose, in the presence of a hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone (HEMP) photoinitiator, to give high modification yields (>90%). Zhang and co-workers investigated cyclic brush-like polymers, that were synthesized by tandem organo-mediated zwitterionic polymerization followed by CuAAC modification with PEG-N3 via a grafting-onto approach.52 Beside poly(Npropargylglycine) homopolymer macrocycles, also cyclic poly(N-propargylglycine-co-N-butylglycine) copolymers were studied. Interestingly, the grafting densities were noticeably higher in the latter case with the copolymer which can be attributed to a facilitated access to the propargyl groups. AFM measurements of cyclic brushlike polymers showed donut-shape-nanostructures with the average diameter of 362 nm for a randomcopolymer and revealed ring-shaped structures for the homopolymer which have a slightly smaller average diameter of 283 nm (Figure 8). The theoretical lateral dimension is approximately seven or eight times lower with respect to the measured values. The authors attribute this to the tip effect in AFM imaging, resulting in overestimation of the lateral features.

Figure 8. Synthesis of amplitude images of homopolymer (bottom right). Reprinted from Society.

cyclic polypeptoid brushes (top) and AFM corresponding donut-shape structures of left) and cyclic brushlike polymers (bottom ref 52. Copyright 2011 American Chemical

More recently, Schlaad et al. demonstrated the great potential of poly(N-propargylglycine) as a versatile platform for post-polymerization modification of polypeptoids (Scheme 10).53 The propargyl side chains were modified using various chemistries such as CuAAC and radical thiol−yne addition. Propargyl anions were produced by deprotonation of propargyl groups with a very strong non-nucleophilic phosphazene base (tBu-P4) and readily added to ethylene oxide. Besides CuAAC click reaction, the obtained triazole linkers were quaternized (to about 80%) with bromoethane yielding the first polypeptoidic ionic liquid. Furthermore, poly(N-propargylglycine) could be cross-linked by simple thermal treatment, through a yet unresolved mechanism, to yield an insoluble amorphous material.177 Kirshenbaum and co-workers prepared precisely functionalized peptoids by sequential CuAAC conjugation reaction on a solid support (Figure 9).178,179 This on-resin click approach was also applied to glycosylated peptoids for antifreeze applications.180 More recently, the group developed an elegant approach to couple therapeutics peptides or proteins with N1765


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Scheme 10. Synthesis of Poly(N-propargylglycine) and Subsequent Modifications of Alkyne Side Chainsa

a

Adapted from ref 53. Copyright 2015 Elsevier Ltd.

Figure 9. Synthesis and sequential CuAAC modification of oligopeptoids. Reprinted with permission from ref 178. Copyright 2006 Royal Society of Chemistry.

side chains (i.e., n-propyl, allyl, and iso-propyl) could be welldissolved in water at 20−40 g L−1 and showed LCST behavior, whereas poly(N-propargylglycine) remained insoluble in water.49 The conflicting reports on the solubility of these polypeptoids can be attributed to the differential solubility of amorphous and semicrystalline samples. The cloud point temperatures (Tcp) were found to increase in the order of npropyl (15−25 °C) < allyl (27−54 °C) < iso-propyl (47−58 °C), depending on chain length and polymer concentration (classical Flory−Huggins type 1 behavior).188 The phase transitions were reversible only for shorter timescales. Longterm (days) annealing of dilute aqueous solutions (0.5 wt %) of poly(N-n-propylglycine) and poly(N-allylglycine) resulted in the formation of crystalline precipitate with complex morphology (see section 2.5.2.2). Furthermore, the cloud point temperatures can be adjusted using statistical copolymers comprising hydrophilic units,

terminal serine units to peptoids with C-terminal salicylaldehyde esters.181 2.5. Physico-Chemical Characteristics of Polypeptoids

2.5.1. Properties in Solution. 2.5.1.1. Thermoresponsive Solution Behavior. Some polypeptoids show lower critical solution behavior in aqueous solution (LCST = lower critical solution temperature), meaning that they are soluble in water at lower temperature and become insoluble at higher temperature, which they have in common with other polyamide structural isomers like poly(methacrylamide)s or poly(2-oxazoline)s.157,182−187 Peptoid homopolymers with methyl (C1, sarcosine) and ethyl (C2) side chains are readily soluble in water while all other polypeptoids with longer alkyl side chains (C3 and longer) were considered to be insoluble.43 Later, Schlaad and co-workers demonstrated that amorphous samples of polypeptoids with C3 1766


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(sarcosine),191 and the double-hydrophilic poly(N-n-propylglycine])-block-poly(sarcosine).191 The latter system turns into an amphiphilic diblock copolypeptoid upon increasing the temperature to above the collapse temperature of the thermosensitive poly(N-n-propylglycine) block (see section 2.5.1.1) to induce micelle formation. Poly(N-alkyl urea peptoid)-graf t-[poly(styrene)-block-poly(acrylic acid)] (36-mer peptoid, Mn ∼ 76 kg/mol) formed particles of about 480 nm in diameter (DLS) in water at pH 8, where the carboxylic acid blocks in the side chains are deprotonated, thus hydrophilic. Particles were thought to be micelles, though a core−shell structure might be excluded by the very large size of the particles and the broad size distribution.192 Inverse micelles of 20−25 nm in size were formed by dialysis of dilute poly(ethylene glycol)-block-poly(sarcosine) solutions against 1,4-dioxane or ethyl acetate.69 The micelles in dioxane were irregular in shape while the ones in ethyl acetate were spherical, as evidenced by TEM (Figure 11). This was

usually sarcosine or N-ethylglycine, and hydrophobic units, usually butyl or higher alkyl chain substituted glycines, at various ratios. Examples include poly(sarcosine-co-N-butylglycine) with tunable cloud points in the range of 27−71 °C (at 0.3 wt % in water; sarcosine content increasing from 42 to 73 mol %)70,189 and poly(N-ethylglycine-co-N-butylglycine) 20− 60 °C (at 0.1 wt % in water).71 For the latter case, Zhang and co-workers found a distinct albeit little impact of the architecture (linear vs cyclic) on cloud point temperatures. The phase transition of the cyclic copolypeptoids was shifted to lower temperature as compared to the linear analogues with the same composition (and same concentration) (Figure 10). This

Figure 10. Cloud point temperatures of linear and cyclic poly(Nethylglycine-co-N-butylglycine) at 0.1 wt % in water as a function of the hydrophilic side chain content in mol %. Reprinted from ref 71. Copyright 2012 American Chemical Society. Figure 11. TEM images of dried/collapsed micelles of poly(ethylene glycol)-block-poly(sarcosine) prepared in (A) dioxane and (B) ethyl acetate. Reprinted with permission from ref 69. Copyright 2014 John Wiley and Sons.

was explained in terms of lower entropic loss. Also, they found that the cloud point temperature decreased upon addition of sodium salts, the degree of depression being in line with the Hofmeister series (i.e., sulfate > chloride > iodide). A similar salting-in/out effect was also observed for poly(sarcosine-co-Nbutylglycine).189 Interestingly, polymer architecture seemed to have no impact on the cloud point temperature when comparing linear norbornyl-poly(N-ethylglycine-co-N-butylglycine) and poly(norbornene)-graf t-[poly(N-ethylglycine-co-N-butylglycine)] bottlebrushes (prepared by ring-opening metathesis polymerization, ROMP).72 However, the phase behavior was strongly dependent on the thermal history of the samples and the presence of inorganic salts. 2.5.1.2. Aggregation Behavior. Here, the aggregation behavior of block copolypeptoids in aqueous and organic solution and of lipopoymers will be addressed. The aggregation of peptoids will be discussed in detail in sections 3.2 to 3.4 (secondary to quaternary structures). Double-hydrophilic poly(ethylene glycol)-block-poly(sarcosine) in water was found to assemble into some small spherical particles of ∼20 nm in diameter (TEM) and unstable aggregates of >90 nm (as determined by dynamic light scattering, DLS).69 Furthermore, it was shown that the copolymer could act as a surfactant and stabilize organic (dichloromethane) droplets in aqueous solution to give stable emulsions. Droplets were larger in size (less curved) the larger the hydrophilic sarcosine weight fraction in the copolymer was. Spherical aggregates in dilute aqueous solution have also been observed for the amphiphilic poly(γ-benzyl-L-glutamate)block-poly(sarcosine),190 poly(N-propargylglycine)-block-poly-

attributed to different solubility parameters for the two blocks in the organic solvents. Interestingly, metal ion salts like copper(II)acetate and nickel(II)acetate could be loaded into the PSR core of the inverse micelles in ethyl acetate, as confirmed by TEM and UV spectroscopy. However, the metalloaded micelles showed great tendency toward cluster formation, as seen in TEM as well as in DLS (revealing a much larger particle size (>300 nm) and polydispersity). Double hydrophilic dextran-block-poly(sarcosine) was found to assemble into micron-sized giant polymer vesicles in water at a concentration of 25 wt %.193 Microphase separation occurs through balancing the osmotic pressure between the two hydrophilic phases containing different amounts of water (dextran binds more water molecules than PSR). Asymmetric poly(sarcosine)-block-poly(N-decylglycine) (100/9 units) were shown to undergo a sol−gel transition in methanol solution.194 The self-assembly process was driven by the crystallization of decyl side chains in the hydrophobic block, leading to a physically cross-linked fibrillar network (5−10 wt % polymer). Interestingly, cyclic polymers built stiffer gels than their linear analogous, as evidenced by rheology measurements, due to different degrees of crystallinity. Reversibility of the process could be shown by DSC and time-resolved WAXS revealing a gel−sol transition of around 60 °C coinciding with the melting of the decyl side chain crystals. Kimura and co-workers showed the self-assembly of poly(sarcosine)-peptide block copolymers (AB, A2B, and 1767


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melting) (Table 1). The main chain melting of the uniform 15mer poly(N-butylglycine), prepared by solid-phase synthesis, was observed at 160 °C.206 The copolymer poly(sarcosine-coN-butylglycine) did not show any crystallization.70 For linear and cyclic polypeptoids bearing linear C4−14 side chains, Zhang et al. found that the side chain melting temperature increased while the main chain melting temperature decreased with increasing side chain length (Figure 12), suggesting that the two crystallization processes were coupled.47 This coupling was further supported by the observation that the main chain crystallization was significantly inhibited for polypeptoids with noncrystallizable ethyl or branched 2-ethylhexyl side chains. Also, the cyclic polymers exhibited higher main chain melting temperatures than the linear analogues, while the side chain melting temperature was not affected. Rosales et al. investigated the effects of structural “disturbances” (i.e., on the crystallization and thermal behavior of short sequence-specific mostly aliphatic peptoids).206 As such, this paper is a perfect example that the boundaries between polymer science and the classic sequence-specific peptoids become more and more blurry. Obviously, the perfect control is not possible with classic polymers. The peptoids investigated comprised exactly of 15 monomer units. With increasing the number of defects (2 or 4), the melting temperature were depressed or crystallization eventually abolished. Using a series of peptoid sequences with exactly 2 defects, the effect of the defect location was studied. Interestingly, the enthalpies of melting was affected quite significantly and varied from 35.5 to 58.3 J/g in the case of [Nisoamylglycine13-co-N-(2-methoxyethyl)glycine2]. The melting points varied from 174 to 166 °C, and the variation did not correlate with the variation in melting enthalpies.206 2.5.2.2. Solid-State Morphologies. Crystal structures of sequence-specific peptoids will be described in section 3.2. Here, semicrystalline solid-state morphologies of (poly)peptoids will be discussed. Such structures have been obtained by long-term annealing of dilute aqueous solutions of poly(N-npropylglycine) or poly(N-allylglycine). The formed precipitate was found to consist of crystalline microparticles having a rose bud type morphology as observed by scanning electron microscopy (SEM) (Figure 13) with melting points of 188− 198 °C and 157−165 °C (DSC), respectively.49 Segalman and co-workers studied AB diblock copolymers with a poly(styrene) segment and a sequence-specific peptoid comprising either 2-methoxyethyl side chains or 2-methoxyethyl/2-phenylethyl side chains.207 The first series of poly(styrene)-block-poly(peptoid) block copolymers readily selfassembled into hexagonally packed and lamellar morphologies, as evidenced by small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) in addition to DSC. In the second series, the presence of styrene-like units along the peptoid chain decreased segregation strength (i.e., increased compatibility) between the two blocks, thus preventing microphase separation leading to disordered structures. Balsara and co-workers presented a systematic study of the relationship between chemical structure and solid-state morphology of uniform comblike poly(N-2-(2-(2methoxyethoxy)ethoxy)ethylglycine)-block-poly(N-(2ethylhexyl)glycine) obtained by solid-phase synthesis.208 The number of monomers per chain was kept at 36, and the volume fraction (ϕ1) of the first block was varied from 0.11 to 0.65. All block copolymer samples, irrespective of the composition, were

(AB)8 type) in aqueous solution to give a plethora of nanostructures, including nanotubes of varying diameter and length, vesicles, and discs.195−202 Structure formation is all governed by the hydrophobic helical peptide block [D-/Lleucine-(2-aminoisobutyric acid)]n (n = 6−16), eventually in combination with stereo complexation (see section 3.4.3). Gervais and co-workers studied the self-assembly of lipopolymers of PSR with aliphatic chains ranging from C12 to C18, respectively using XPS.203,204 The degree of polymerization of the PSR block was varied from 1 to 91. For less than four units, sarcosine units were added in a stepwise manner. Depending on the PSR degree of polymerization, thin films cast from solvents exhibited lamellar, hexagonal, or body-centered cubic structures. Domain sizes ranged from a few Ångström to several nanometers. Liquid crystals of lipo(amino acids) were studied by Gallot and co-workers.205 Herein, the lipid part constituted alkyl chains of C12 to C18 and was modified with various amino acids (for example serine, alanine, and lysine) and sarcosine. It was reported that the liposarcosine only exhibited lamellar liquid crystalline states in the presence of a few percents of water. 2.5.2. Bulk Properties. 2.5.2.1. Thermal Properties. The glass transition temperatures (Tg) of polypeptoids with aliphatic side chains depend on the length of the main chain, as well as of the side chain. The Tg of PSR is highest with 127− 143 °C and is continuously decreasing for homologues with longer side chains.54 Tg values below room temperature were measured for poly(N-n-butylglycine) and poly(N-n-pentylglycine) by differential scanning calorimetry (DSC) (Table 1). Polypeptoid samples were found to be thermally stable up to 200−250 °C, by thermogravimetric analysis (TGA).70 Table 1. Glass Transition and Melting Temperatures of (Poly)peptoids (Data Taken from Refs 39, 47, 54, and 206) (poly)peptoid Nalkyl C1: methyl C2: ethyl C3: n-propyl C3: iso-propyl C3: allyl C3: propargyl C4: n-butyl C5: n-pentyl C5: iso-amyl C6: n-hexyl C8: n-octyl C8: 2-ethylhexyl C10: n-decyl C12: n-dodecyl C14: n-tetradecyl N-aryl = C7: 2-phenylethyl

Tg (°C)

Tm,1 (°C) side chain

Tm,2 (°C) main chain

127−143 77−114 34−93 121 50−64 108 4 −5 to −3 n.d. n.d. n.d. n.d. n.d. n.d. n.d.

n/a n/a n/a n/a n/a n/a (−65) 63−70 49−67 n/a n.d. 53 n/a 72−79 84−90 100

n/a n/a 163−198 n/a 150−170 n/a 153−225 145−207 180 145−160 130−187 186 166−176 157−166 140

70

n/a

225

Peptoid homopolymers are amorphous or semicrystalline materials depending on the length of the side chain. PSR (C1) and poly(N-ethylglycine) (C2) are amorphous, while the higher homologues (linear C3 and longer) are semicrystalline. Poly(Nn-propylglycine) exhibits a single melting transition at Tm = 163−198 °C,49,54 while poly(N-n-butylglycine) and homologues with longer side chains exhibit two melting transitions at 49−79 °C (side chain melting) and at 130−225 °C (main chain 1768


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Figure 12. DSC thermograms of cyclic (left) and linear (right) polypeptoid homopolymers during the second heating cycle (n = number of carbons on the alkyl side chain). Reprinted with permission from ref 47. Copyright 2013 American Chemical Society.

methoxyethoxy)ethoxy)ethylglycine) and poly(N-decylglycine)-block-poly(N-2-(2-(2-methoxyethoxy)ethoxy)ethylglycine) with 18 units per block also produce lamellar structures.210 Interestingly, the oligoether block can dissolve lithium ions and is amorphous in the first case (when bound to the amorphous poly(N-(2-ethylhexyl)glycine) block) but crystalline in the second case (when bound to the crystalline poly(N-decylglycine) block). Cyclic peptoid sequences have been shown to form supramolecular assemblies by coordinating sodium ions very similar to metal organic frameworks (MOFs).211 Hence, peptoids could be used as tunable linker for commonly used MOFs. Two out of three investigated molecules crystallized and showed different solid-state properties, despite minor differences in the molecular structure. In contrast, the third structure did not crystallize. A similar structure, which could be used for completely different applications, was described by Kirshenbaum and co-workers.212 By alternating pairs of cis- and transamide bonds in the backbone of a cyclic peptoid octamer, a selfassembling peptoid was obtained. Nanotubular crystal structures with associated water molecules were observed (Figure 14). Since diffusion of the water molecules through the nanotubes was indicated and the nanotubes could withstand temperatures of 300 °C, possible applications in the field of microelectronics, biosensors, or nanotechnology were suggested.

Figure 13. Scanning electron micrographs (of crystalline poly(N-npropylglycine) (left) and poly(N-allylglycine) (right), obtained by annealing of 0.5 wt % aqueous polymer solutions at 75 °C (60 h) or 70 °C (24 h), respectively. Adapted from ref 49. Copyright 2013 American Chemical Society.

found to assemble into a lamellar morphology, and the experimentally determined order−disorder transition (ODT) temperature exhibited a maximum at ϕ1 = 0.24, instead of 0.5 as expected from theory.209 The phase behavior of these peptoids is in disagreement with theories of microphase separation in block copolymers, which raises general questions about the roles of architecture and dispersity in the phase behavior of diblock copolymers. Similarly, ethyleneoxy-containing diblock copolypeptoids of poly(N-(2-ethylhexyl)glycine)-block-poly(N-2-(2-(21769


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Figure 14. (a) Chemical structure of the cyclic peptoid octamer. View along the (b) and (c) axes of the crystal lattice (three peptoid oligomers are shown). Adapted with permission from ref 212. Copyright 2013 Royal Society of Chemistry.

3. INTRAMOLECULAR AND INTERMOLECULAR ASSEMBLY OF (POLY)PEPTOIDS Nature demonstrates its abilities in terms of complexity in the evolution of proteins: polypeptide/protein structures are highly diverse, functional, and hierarchical. In the search of alternatives that allow combining such complexity and functionality with synthetic chemical diversity, different strategies can be found in literature. Toward the formation of higher-order structures (e.g., tertiary and quaternary), one might have to control the building block (monomer) sequence itself, like nature does through the protein biosynthesis. Since the stepwise synthesis on the solid support (see section 2.2.1) is one of the very few synthetic ways to generate polymers with perfect sequence control, a small number of scientists have focused their work on the design of two- and three-dimensional peptoid structures mimicking patterns observed in nature. The synthetic strategies toward this goal are described in this chapter, starting from the control of the primary structures, over secondary structures like helices and sheets, which are the fundamental structure elements en route for synthetic proteins, and finally to tertiary and quaternary structures. 3.1. Controlling and Modifying the Primary Structure

Figure 15. Overview of different peptoid backbone variants. General structure of α-peptoids as a reference.

Controlling the primary structure of a polymer, or in other words, the exact sequence of monomer units is the key role for structures with hierarchical order. As described in section 2.2.1, Zuckermann et al. pioneered with the submonomer synthesis the field of sequence-defined peptoids.40 Besides the traditional α-peptoids and β-peptoids, efforts have been made to alternate the backbone to access additional conformations and properties. Different peptoid analogues, like urea peptoids,213,214 hydrazine azapeptoids,215 peptoid hydrazides,216 and aminoxy peptoids217 have been synthesized (Figure 15), although only with low molecular weights. However, most of those functional monomers are compatible with the standard procedure by Zuckermann et al. and could potentially be incorporated into the fully automated syntheses of larger polymers. Additionally, Kodadek et al. used a modified submonomer solid-phase synthesis to generate peptoids with side chains on the α-carbon and nitrogen atom in the backbone to give those polymers a peptide- and peptoid-like character.218 A very interesting modification to enhance the backbone variety was introduced by the Kodadek group by incorporating cyclic monomer units, such as thiazoles, oxazoles, and pyrazine residues (Figure 15).219 This variation introduces conformational constraint into the peptoids, which are usually more flexible than the analogous peptide sequences. The authors

could modify and optimize the submonomer solid-phase synthesis for their system in which they used heterocyclic halomethyl carboxylic acids as a reagent to create diverse oligomer libraries. The authors suggest that these libraries can be used to screen different biological targets to find structurally diverse ligands. More recently the same group also reported on the integration of 2-oxopiperazine into the peptoid backbone (Figure 15).220 In contrast to their former work, the heterocycles were not introduced as heterocyclic building blocks but rather formed on the solid support by intramolecular cyclization under basic conditions between the amine-functionalized side chain and the chloroacetylated N-terminus. Another approach to introduce more conformational constraint to enable new applications in molecular recognition and self-assembly is the cyclization of the linear chains themselves. Zhang et al. discovered the NHC-mediated polymerization of NNCAs to give polypeptoid macrocycles, and a few groups have worked on cyclization of peptoids either directly on solid support or after cleavage in solution (as discussed in section 2.4.1). Very recently, Kwon et al. synthesized equivalent structures in cyclic and linear form to study and compare directly their biological activity.136 Besides linear and cyclic structures, branched architectures like tripodands221 or dendrimers222,223 have been reported 1770


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strated by fluorescence energy transfer studies.227 Therefore, specific synthetic strategies are necessary to favor one of these conformations depending on local intramolecular interactions to induce secondary structures. 3.2.1. Controlling cis/trans-Conformation. Early studies of Sisido et al.129 showed the solvent-dependent cis/transisomerization of the polypeptoid backbone and, much later, Sui et al.228 confirmed this isomerization and its energy barrier. Since, many groups set their aim toward the specific promotion of either cis or trans via steric or electronic effects of the side chain and/or interactions between side chain and backbone. In contrast to the works by Sisido et al. and Sui et al., which dealt with polypeptoids, the later studies were all performed with peptoids. It has been shown that peptoids with Cα-chiral substituents favor cis-conformation (Figure 17).229−231 Alternatively, cis-

(Figure 16). Wessjohann et al. showed with their multiple multicomponent assembly process toward peptide-peptoid

Figure 16. Example of a cholane-armed podand synthesized via Ugi multicomponent reaction, which exhibits a potential as a molecular umbrella for the transport of biomolecules across membranes. Reprinted with permission from ref 221. Copyright 2013 Wiley-VCH.

podands the possibility to cover a wide and diverse chemical range of podands and topologies in a highly modular one-pot approach that is even suitable for automation. Wessjohann pioneered the use of the Ugi-reaction to obtain peptoid-peptide hybrids. Interesting to note, the Ugi reaction has very recently also been applied to obtain peptide/peptoid hybrid polymers.224−226 These fill a unique niche, as they are sequencespecific but at the same time nonuniform in their chain length. Bradley and co-workers synthesized three generations of peptoid-based dendrimers via microwave-assisted solid-phase synthesis and proved the third generation compound as efficient mediator of transfection with minimal cytotoxicity.222 More recently, Bräse et al. used click chemistry to form rigidsoft nanostructures with aromatic cores and peptoid arms as the outer rim.223 The solubility of these products could be tuned by using different cores. Moreover, polymer brushlike structures have been prepared via functionalization of peptoid scaffolds.178 As described above, peptoid chains can be synthesized in a well-defined manner, which allows the control of the fundamental architectures in the form of linear, branched, or cyclic oligo- and polymers, to introduce hundreds of different side chains and even diverse molecules into the backbone. The possibility to place specific side chains into defined positions and distances from each other to form intra- and intermolecular interactions now gives rise to higher ordered structures. The possibility to combine this tight control over the primary structure with the polymerization on the solid-phase opens up unique possibilities in macro- and supramolecular engineering, which are yet to be explored.

Figure 17. Demonstration of the two different conformational states of the amide bond in the peptoid backbone, cis and trans. The arrow indicate the stabilizing n → π*Ar and n → π*co interactions for the cis- and trans-conformation, respectively. Below, the residues that induce the corresponding conformation are pictured: bulky aromatic (and tert-butyl, not shown) for cis and aryl, hydroxyl, and alkoxy for trans.

conformation can be provoked by purely steric effects (e.g., by introducing tert-butyl side chains)232 or by incorporating aromatic side chains that lead to favorable interactions between their substituent electron orbitals and the orbitals of the backbone. This was possible by the use of N-α-chiral acetanilide or N-1-naphtylethyl substituents due to n → π*co and hydrogen bonding, or n → π*Ar and steric interactions, respectively (Table 2).233 Remarkably, the cis-conformation could only be found in polar solvents, while nonpolar solvents favored the trans-conformation. This could be an interesting approach toward structures that can fold depending on their environment. For positively charged α-chiral methylpyridine side chains, 89% of the amide bonds were found to be in cisconformation. Further studies characterized the n → π*Ar stabilization in detail and distinguished between this and a newly described “bridged n → π*Ar” interaction.234 Here, an electron density transfer from the amide to the aromatic ring takes place, and this transfer is enabled by an intermediary δ* orbital. It was shown by theory and experiment that this interaction appears to be most significant for electron-rich, neutral, and moderately electron-poor aromatic side chains. Computational analysis predicted that electron-deficient

3.2. Mimicking Secondary Structures

Secondary structures in proteins are well-described and have been successfully predicted after Pauling, Corey, and Branson developed a model for peptide α-helices in 1951.240 Further investigations showed that most homopolymers of natural amino acids tend to form either α-helices or β-sheets.23 Homopolymers of sarcosine, on the other hand, exhibit a disordered random coil formation in water41 and are also soluble in a wide range of organic solvents.43 In contrast to (poly)peptides, the backbone of (poly)peptoids is inherently flexible and does not favor cis- or transconformation of the amide bond,129 whereas most of the peptide structures feature predominantly the trans-conformation. Moreover, PSR chains are very flexible (more so than oligo-proline chains) in (ethanolic) solution, as was demon1771


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Table 2. Kcis/trans Values for Different α-Chiral Aromatic Side Chains, As Determined By 1H−COSY and HSQCAD NMR in CD3CN at 24 °C (Data Taken from Refs 233, 247, and 253)

a

Weighted average of Kcis/trans for all residues. bMeasured at 25 °C.

Figure 18. Predicted helical structure of N-(1-phenylethyl)glycine octamer peptoid viewed (a) parallel and (b) perpendicular to the long axis of the PPI-like helix. Peptoid backbone atoms are color-coded (green, carbon; gray, hydrogen; red, oxygen; blue, nitrogen); side chain atoms are depicted in yellow. Adapted from ref 229. Copyright 1997 Elsevier Ltd.

aromatic side chains would stabilize the cis-conformation of the amide bond rather by the direct n → π*Ar interaction. Combining chemical synthesis, NMR spectroscopy, and Xray crystallography, Olsen and co-workers investigated the effect of thioamides and/or fluorides in peptoid monomer model systems.235 They described the steric environment of the amide bond as key promoter of conformational orientations. Most interestingly, their results of X-ray crystallography indicate that stabilizing n → π*co interactions only occur when carbonyls were altered electronically by thioamide formation or α-halogenation. Further, the authors suggest that these backbone alterations may be used to stabilize

secondary formations such as poly(L-proline) type I helices (PPI, see next section 3.2.2). Trans-amide conformation is favored by aryl substituents that are directly bound to the nitrogen atom in the backbone.236 Shah et al. synthesized peptoids comprising two to six monomer units and evaluated the relative energies of cis- and trans-amide bonds by computational methods. It was shown that a broad set of aryl substituents were tolerated for the energetic preference for trans-amide bond conformers. Solution NMR spectroscopy and X-ray crystallography of these N-aryl peptoids confirmed the preference of the amide bonds in the backbone toward the trans-conformation. 1772


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Figure 19. Predicted helical structure of N-phenylglycine peptoid hexamer viewed (a) parallel and (b) perpendicular to the long axis of the PPII-like helix. Atoms are color-coded (gray, carbon; white, hydrogen; red, oxygen; blue, nitrogen). Adapted from ref 236. Copyright 2008 American Chemical Society.

Besides the mentioned aryl substituents, hydroxyl, and alkoxy substituents lead to the preference of trans-amide conformation as well.237,238 Jordan et al. recapitulated their experimental investigations with quantum mechanics calculations and studied the backbone and side chain torsional energies. Further, they could show via circular dichroism and NMR spectroscopy that longer peptoids preserve the overall order of the dimer. Upon the basis of these results, they designed a model of the secondary structure, which is formed by an N-alkoxy peptoid. Interestingly, the resulting poly(L-proline) type II helix (PPII, see next section 3.2.2) demonstrates a resemblance to the above-mentioned N-aryl peptoids. In contrast to this, Nhydroxy amide side chains promote sheetlike structures, which will be discussed in section 3.2.3. 3.2.2. Helices: Multifaceted Structural Elements. Helices are very common secondary structures in proteins, were the first to be discovered and represent the most intensively investigated motifs besides β-sheets.239,240 In peptides, such structures are stabilized through hydrogen bonds. However, poly(L-proline) has been known for many years to form two distinct types of helices, so-called poly(Lproline) type I helix (PPI) and poly(L-proline) type II helix (PPII).2,241,242 Therefore, it was interesting when first circular dichroism (CD) spectra showed that peptoids bearing Cα-chiral side chains exhibit similar curves like α-helices with a double peak at 203 and 220 nm.243 This data was later supported by computational studies that suggested the formation of helices similar to PPI (Figure 18), with a pitch of approximately 6 Å and a periodicity of three residues per turn.229 Moreover, the asymmetric Ramachandran-like plots that have been shown in this work indicate that the handedness of the helix can be controlled by the handedness of the side chains. Initial and systematical investigations by Barron and coworkers examined the dependence of the helix stability of a monomer sequence using chiral aromatic side chains.244,245 Peptides comprising helicogenic amino acids form initially βsheets (number of repeat units, DP ≤ 10) before they form helical structures.23,246 In contrast, helices formed by heliogenic peptoids can be found for oligomers as short as five monomer units.244,245 Its stability increases up to a DP of 15. A minimum of 50% Cα-chiral side chains are necessary to form stable helices as well as a chiral aromatic side chain at the C-terminus. Astonishingly, those helices were stable up to 75 °C, and the impact of the described requirements became less important with increasing chain length. Interestingly, a similar stability was found for water-soluble helices of chiral poly(2-oxazoline)s.39

Further studies showed that aromatic residues are not necessarily required to form helices.247 In this work, Baron and co-workers showed the first crystal structure of a peptoid helix with a pitch of approximate 6.7 Å, three residues per turn, and a left-handedness which is comparable to PPI. Recently, Seo et al. could verify the importance of a chiral aromatic side chain at the C-terminus and pointed out that a α-chiral residue at the second position from the N-terminus has a major impact on the formation of secondary structures as well.248 They investigated peptoid heptamers and described the “existence of lynchpin-like structure-inducing positions” and positions in the sequence that are uninfluential (i.e., the first, fourth, and sixth positions from the N-terminus). Interestingly, they could induce helices with only one α-chiral residue at the second position from the N-terminus. This work shows the tremendous importance of sequence control to form secondary and, in perspective, protein-like structures, which makes the submonomer solid-phase synthesis an indispensable tool on this route toward synthetic biology or defined functional material. Remarkably, in 1963 Fasman and Blout made a similar observation, that 50% chiral monomer units are necessary to obtain helices when copolymerizing L-proline (helicogenic) and sarcosine (nonhelicogenic), which leads obviously to nonuniform polypeptoids.249 Later, similar helices were also described for homopolymers obtained by NHC-catalyzed ROP of NNCA.250 In our opinion, this can be seen as a nice demonstration of the blurred borders between peptoid design and supra- and macromolecular engineering with polypeptoids. Since peptoid helices cannot be stabilized by hydrogen bonding via the backbone, mixed impressions about their stability can be found in literature. It was shown that the peptoid helices are stable against most denaturants (e.g., urea and temperature),251 but conformational stability is typically less than that of peptide α-helices. This is marked by low Kcis/trans values and rather short persistence lengths.244 Depending on the chain length, values range between 1 and 4 nm for peptoid helices. SANS studies indicate that the persistence lengths of helices induced by bulky α-chiral 1-phenylethyl side chains were only longer for short sequences and showed almost no difference for longer ones compared to peptoids with the same number of monomer units but achiral phenethyl side chains.252 However, due to these rather short persistence lengths, the authors suggest that the polymer chains maintain considerable conformational freedom. Incorporation of bulky residues stabilizes these helices sterically233,253 and especially a N-1-naphtylethyl side chain leads to high Kcis/trans values 1773


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Figure 20. Structure of Rhodamine B-labeled peptoid and its structure assembly as obtained by a QM/MM (quantum mechanics/molecular mechanics) refinement using a COSMOS-NMR force field that forms an extended helix formation. 1H−13C-HSQC spectrum in 90% H2O/10% D2O depicted on top of the arrow. Reprinted with permission from ref 262. Copyright 2013 Royal Society of Chemistry.

biological activity, which was shown by the cellular uptake of the peptoid, was similar to other cell-penetrating peptides. Kang et al. used peptoid helices as scaffolds to precisely control the orientation of porphyrins. In this manner, they investigated cofacial, slipped-cofacial, and unstructured array of porphyrins and showed that the distance, orientation, and number of the porphyrin-peptoid conjugates had a huge impact on the degree of J-aggregation, resulting in color and excitonic coupling.263 The authors speculate that these structures might be interesting for the design of artificial photosynthetic complexes. Olsen and co-workers were very recently the first to report on stable helical structures designed by β-peptoids (Figure 21).264 X-ray crystal structures of β-peptoid hexamers

without affecting the overall helix structure (Table 2). As discussed in the previous chapter, N-aryl residues promote a trans-conformation in peptoids. Kirshenbaum and co-workers applied N-phenylglycine monomer units in a peptoid hexamer and confirmed the predicted structure of PPII-like helices (Figure 19).236 Additionally, approaches to functionalize peptoid helices have been reported to either modify the solubility, promote formation of higher-order structures, to generate a pHresponsive conformational change, or to further improve their stability.134,254−257 Also 4-azidoproline, as intermediate between peptides and peptoids, was used by Wennemers and colleagues to form helices.258 Interestingly, while the 4Renantiomer stabilizes PPII, its 4S-enantiomer destabilizes it. Kirshenbaum et al. introduced alkyne and azide groups at i and i+3 positions of helicogenic sequences to stabilize helical structures even in short oligomers after “clicking” both side chains (Figure 5b).134 Remarkably, in this manner, the synthesized cyclic peptoid sequences yielded more intense circular dichroism spectra as compared to their linear pendants, suggesting more stable helices. Similar differences in stability were found for cyclic and linear polymers.250 Although, less helicogenic residues have to be incorporated via this approach, at least two modified building blocks are needed to stabilize the helix. A different approach to incorporate functionalities was described by Zuckermann et al.257 They introduced 1phenylethyl residues with functional groups (thiols, carboxylic acids, and amides) in the para-position of the phenyl ring, which localizes them at the outer perimeter of the formed helices. This allows for the mimicking of the interactions between helix bundles in proteins and α-helices in coiled coils.259−261 In order to generate cell-penetrating structures, Bräse, Muhle-Goll, and co-workers incorporated butylamine as lysinelike residues into peptoids and revealed an extended pseudohelical structure via quantum chemical calculations and NMR spectroscopy (Figure 20).262 This extended helix with a pitch of 7.7 Å was explained by electrostatic repulsion between the side chains to maximize the spacing of the ammonium groups. The amide bonds in the backbone were found to be predominantly in cis-conformation and the charge distribution less dense compared to peptide analogues. However, the

Figure 21. Helical structure of (a) N-(S)-1-(1-naphthyl)ethyl βpeptoid hexamer. (b) End view shown as stick representation. (c) Side view of the X-ray crystal structure shown in light gray and the conformation after 1 μs MD simulation shown in blue. Only the backbones are shown as sticks to highlight the similarity. Reprinted with permission from ref 264. Copyright 2015 Macmillan Publishers Limited. 1774


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Figure 22. (a) Peptoids that form intermolecular β-sheet-like structures. (b) Partial 1H NMR and ROESY spectra [blue arrows point to the observable minor conformational peaks, and the red boxes highlight a weak ROE between the NT-H and ac1-Hα backbone protons (right box), as well as the absence of an observed ROE between the ac1-Hα and ac2-Hα backbone protons (left box)]; (c) X-ray crystal structure depicting five molecules of the peptoid in a sheetlike hydrogen-bonded network. The solid green lines indicate H bonds, and the black dashed line indicates the intermolecular ac1-Cα-ac2-Cα distance. Reprinted from ref 238. Copyright 2011 American Chemical Society.

Figure 23. Peptoid ribbon structure. (a) An ensemble of ten superimposed low-energy structures of a ribbon forming peptoid hexamer as determined by NMR spectroscopy. (b) Axial view down the N-terminus showing the left-handed spiral of this ribbon conformation. Reprinted with permission from ref 268. Copyright 2013 Wiley-VCH.

containing N-(S)-1-(1-naphthyl)ethyl side chains revealed a right-handed helical conformation with a helical pitch of 9.6− 9.8 Å and 3 residues per turn. Further, molecular dynamics simulations support those stabilized secondary structures in organic solvents. 3.2.3. Sheet, Ribbon, Turn, and Loop. Besides α-helices other predominant structure elements in proteins are β-sheets. Blackwell and co-workers demonstrated that peptoid dimers with N-hydroxy amide side chains could be crystallized, and the X-ray crystallographic data exhibits sheetlike structures (Figure 22).238 On top of the fact that the employed side chains promote trans-conformation of the amide bond, they are also prone to hydrogen bonding, which both were found to be necessary for sheet formation in proteins.265 Although, they suggested that incorporating N-hydroxy amides into longer peptoids may lead to the formation of peptoid β-sheets, the synthesis of such sheets consisting of only one individual chain has not been reported. Zuckermann and co-workers could also show sheetlike structures within the structure of their two-

dimensional crystalline nanosheets, which will be discussed in more detail in section 3.4.1.266 Interestingly, powder X-ray diffraction (XRD) analysis revealed a spacing between the peptoid chains of 4.5 Å, which is close to the commonly found 4.7 Å in peptide β-sheets.267 Recently, Blackwell and co-workers designed a peptoid ribbon structure.268 Ribbons can also be found in proteins and could function as antibiotics or cell-membrane modifying agents. The peptoid structure was realized by alternating bulky α-chiral naphthyl- and N-arylglycine residues and therefore alternating cis- and trans-conformation of the amide bond, respectively (Figure 23). Similar to peptide ribbons, it exhibits a helical conformation parallel to the backbone with a helical rotation of 36°. Interestingly, n → π*co interactions, which usually play a significant role in helical conformations, are not important for the formation of this structure. The stability of the ribbon in polar and protic solvents could be shown by circular dichroism (CD) spectroscopy studies in methanol and acetonitrile/water mixture. The backbone of the ribbon can be 1775


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Figure 24. As evidenced by (a) CD spectroscopy, the secondary structure of N-1-phenylethylglycine oligomers depends strongly on the number of repeat units. Whereas Nspe6 and Nspe12 form helical structures, Nspe9 forms a (b) loop as depicted in a cross-eyed stereographic view of the ensemble of 20 NMR structures following a best-fit superposition of the backbone atoms. Reprinted from ref 278. Copyright 2006 American Chemical Society.

Figure 25. Energy landscapes for a trans-sarcosine dipeptoid in vacuum from quantum mechanics (left) and simulations of the force field (right) demonstrate the accuracy of the latter. Reprinted with permission from ref 288. Copyright 2014 Wiley Periodicals, Inc.

pictured as sequence of turns, which is also observed in peptide ribbons.269 In fact, turns are, just as loops, another fundamental structure element in proteins,270−275 and being able to mimic those structures would be an important step toward the synthesis of proteinlike assemblies. In the two different approaches to realize a single turn in a peptoid sequence, it was necessary to alter the backbone itself.276,277 Apella and co-workers introduced a triazole ring that induces a hairpinlike motif, which was also confirmed in aqueous solution.277 Blackwell and co-workers on the other hand attached a monomer unit that was able to form hydrogen bonds onto the side chain of a tripeptoid.276 With this, however, one may argue that unique character of peptoid-based structures (i.e., the nonhydrogen bonding) is lost to some degree. Moreover, Barron, Radhakrishnan, and co-workers reported on a peptoid sequence that forms a so-called threaded loop structure.278 In this study, 1-phenylethyl (Nspe) residues were employed, which were earlier discussed as helicogenic side chains. The interesting fact is that upon increasing the chain length from 6 to 9 units, the CD spectra suggest a change from a helix to a loop structure. Prolonging the chain even further to 12 monomer units indicated again a helical structure (CD) (Figure 24). Astonishingly, instead of an expected all-cis-

conformation, the nonamer features four amide bonds with trans-conformation. Yet, hydrogen bonding is the main driving force to form the loop, which stands, similar to one of the turns, in contrast to the typical peptoid secondary structures without hydrogen bonding. Interestingly, these structures can be destabilized by hydrogen-bonding solvent, which offers the possibility to create a structural building block that can respond to changes in its environment (e.g., solvent or another peptide). Later, Gorske and Blackwell reported a different folding behavior by introducing fluorinated aromatic residues. They demonstrated that only one monomer unit of a 1pentafluorophenylethyl at the N-terminus of a peptoid nonamer stabilizes the loop and that the addition of methanol (protic solvent) did not significantly affected the loop structure.254 A few years later, Blackwell et al. showed the major impact toward the formation of secondary structures of small changes in the monomer sequence.279 A single 1(nitrophenyl)ethyl moiety at the N-terminus of a peptoid octamer of Nspe was introduced. Remarkably, the threaded loop was either destabilized or stabilized depending just on the position of the nitro group (2- or 4-position at the phenyl ring, respectively). Besides, first studies to exploit secondary structures for applications have been reported: 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) was incorporated into 1776


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Figure 26. (a) Protein-like and repeating sequence of peptoid 100-mers. Using molecular dynamics, proteinlike peptoid sequences were obtained by iterative process of globule formation and addition/redistribution of polar residues on the globule surface. (b) Globule-to-coil transition was induced by titration with acetonitrile, which leads to unfolding of the globules. (c) The transition is more pronounced and sharper in the case of the proteinlike sequence. Reprinted from ref 298. Copyright 2012 American Chemical Society.

and the overall structure was described as pseudohelical. However, a full characterization of the three-dimensional structure via this semitheoretical approach was not possible. In contrast to this, Bonneau and co-workers added the peptoid backbone to the Rosetta platform, which is usually used for protein modeling, to allow for complete theoretical simulations of peptoid structures.289 Together with Kirshenbaum and coworkers, they used this option to generate an in silico library of peptoid foldamers with over 50 different side chains.290 Nandel et al. simulated different peptoid structures and showed that a sequence, which favors cis-amide bond geometry can adopt degenerate conformations with alternate dihedral angles (φ, ψ values) of inverse-PPI and PPI type helices or vice versa in water and also inverse-PPI structures in DMSO.291 They also modeled a sequence with alternating trans- and cisamide bond geometry which lead to inverse-PPII and PPII type helices depending on the incorporated side chains. Higher-order structures are important for catalytic activity in enzymes. Therefore, researchers did not stop attempting to mimic secondary, but also tertiary and quaternary structures. The next section will show, that in a few instances, those efforts have already proved successful. Very recently, Whitelam et al. also used theoretical modeling to investigate time-dependent interactions of peptoid chains that can assemble into nanosheets (will be discussed in section 3.4.1).292 Via coarse-grained sites to model peptoids, they were interested in elucidating the fundamental interactions that are necessary for supramolecular assembly. The authors plan to use this model for further investigations of large-scale dynamic processes, which are involved in the preparation cycle of these peptoid nanosheets.

a peptoid heptamer, which showed a promising potential for enantioselective catalytic transformations.280 β-Peptoids are also known to form secondary structures.98,281−285 However, the solubility of the β-peptoids seems to be, here again, the limiting factor, and one may hypothesize that the formation of secondary structures is just a contributing factor to this poor solubility. Yet, this remains to be elucidated. 3.2.4. Computational Modeling. Although, research in the field of peptoid-based secondary structures has made significant advantages over the last years, a lot of issues are still unsolved. Within all the different side chains, configurations, and conformations of peptoids that have been discussed above and the further possibilities that remain to be described, the variety seems infinite. However, since resources are limited in laboratories, computational modeling has been a promising and helpful tool for rapid and cost-effective screenings of designs and discoveries of new sequences and brings therefore synthetic peptoid-based materials one step closer toward biological polymers. After early approaches via Rachmandran-type plots that indicated the great conformational diversity of the peptoid backbone,89 molecular mechanics calculations indicated the impact of the side chains on the backbone conformation229 and on the dihedral angles.286 The first de novo structure prediction was presented in 2012.287 More recently, Mirijanian et al. used a different approach via a first-generation atomistic force field for their simulations of the peptoid backbone.288 On the basis of a CHARMM simulation force field of peptides, a method to demonstrate the solvation effect of water toward the conformations of a sarcosine dipeptoid was developed (Figure 25). Although these modeling studies only consider small molecules, the authors suggest that similar to peptide and protein modeling, the modeling progress will advance rapidly within the next years toward more complex structures. Bräse and Muhle-Goll used COSMOS-NMR to model structures without specific force fields.262 The amide bonds of a labeled cell-penetrating hexamer peptoid were found to be in all cis-conformation,

3.3. Mimicking Tertiary Structures

The term tertiary structure in proteins refers to the threedimensional assembly of one single polypeptide chain into its protein domains, which can comprise one or more secondary structures and is therefore critically determined by its primary sequence. This section will discuss efforts that have been made to mimic such tertiary structures with peptoids. 1777


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Figure 27. Schematic illustration of the formation of the two-helix “bundle” by adding zinc ions. Reprinted with permission from ref 301. Copyright 2008 American Chemical Society.

Figure 28. Nanosheets formed from single-chain peptoid sequences. (a) Alternating charge and (b) block charge sequences is essential (color-code: yellow, carbon; red, oxygen; blue, nitrogen). Imaging of morphology of (c) alternating charge sheets by fluorescence optical microscopy and of (d) block charge sheets by scanning electron microscopy. Reprinted with permission from ref 303. Copyright 2011 Wiley-Blackwell.

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3.4.1. Peptoid Nanosheets. Very intriguing quaternary structures of peptoids are the so-called nanosheets (Figure 28), two-dimensional crystals, prepared and intensively investigated by Zuckermann and co-workers.266 Those sheets are formed by combining peptoid chains (e.g., 36-mers) with alternating cationic/hydrophobic and anionic/hydrophobic residues, respectively. Mixing peptoids with the same architecture but opposite charge leads initially to the formation of globular aggregates. Interestingly, after a few hours, large but ultrathin sheets with a thickness of 27 Å are formed in high yields. Aberration-corrected transmission electron microscopy evidenced that the polymer chains were highly extended within this structure. These first studies were followed by an approach that highlighted the enormous aspect ratio and relatively simple and straightforward preparation of those sheets by mixing and rocking of the peptoid solutions,302 where the sheets are formed via compression of the peptoid monolayer at the air− water interface. Interestingly, incorporating the two different functionalities in a block-wise or alternating manner into one polymer chain, does also lead to similar sheet formation,303 as long as the hydrophobic and ionic side chains were strictly alternating. Since the aggregation of those chains is dependent on hydrophobic and electrostatic interactions, the sheet formation itself depends on the solution pH. Thus, organic solvents can disturb the hydrophobic interactions and lead to destruction of the sheets. Further studies concentrated on the formation of nanosheets at the interface between water and hydrophobic solvents.304 Here, the formation of peptoid nanosheets at the interface of water and pentane, hexane, or heptane could be shown but not at the interface with more viscous (decane and mineral oil) or aromatic solvents (benzene and toluene). Carbon tetrachloride was shown as another solvent promoting the formation of sheets, albeit much smaller ones. The authors suggest interactions between the solvent and the peptoid chains, which influence the collapse into the nanosheets. To gain more insight into the mechanism of the sheet formation, Sanii et al. studied the packing and organization of the peptoid chains and discovered that this takes place during the formation of the monolayer at the water−air surface, prior to the collapse into its bilayer.305 Grazing-incidence X-ray scattering revealed this monolayer exhibits a well-defined structure. As discussed above (see section 3.2.4), coarse-grained models were used for a further understanding of the conformation and behavior of the backbone and side chains within the nanosheets.292 Zuckermann and co-workers already showed in their first studies the possibility of incorporating functionalities into peptoid nanosheets.266 A streptavidin binding peptide was introduced at the N-terminus of the peptoid chains and after the assembling into sheets, they were bound to a streptavidinfluorophore conjugate. Later, they continued this work and were able to incorporate enzyme substrates and gold ligands into the sheets.306 These introduced functionalities are forming loops, which are extending from the plane of the bilayer, and were characterized in a Langmuir trough by X-ray reflectivity. It was shown that the protease labile loops could be cleaved by proteases, loops bearing substrates for kinases were phosphorylated thereby, and the gold ligand loops could be used as template for the growth of gold directly on the nanosheet surface. These studies demonstrate the possibility to rationally design and create three-dimensional architectures that are

3.3.1. Globular Structures. In proteins, hydrophobic interactions are an important driving force in the folding of the polypeptides.293−297 Zuckermann et al. studied this chain collapse, the coil-to-globule transition, of peptoid 100-mers and were able to identify its main cause on the folding as hydrophobic effects and rule out any hydrogen bonding and secondary structures.298 Two different monomer sequences of peptoids with ionic and nonionic monomer units were investigated (Figure 26). One had a regular distribution of the two repeating units and the other consisted of blocks of each residue, designed as “protein-like” using models described by Khokhlov and Khalatur.299 When investigating the coil-toglobule transition, SAXS and dye incorporation revealed that this proteinlike sequence collapses to a more compact globule. Further, the collapse occurred in a smaller window of solvent composition, giving an additional indication of a decreased stability for the repeating structure. 3.3.2. Multihelical Bundles. Another important tertiary structure in transmembrane proteins are bundles of helices. In a combinatorial approach, Zuckermann and co-workers screened through 3400 different 15-mer peptoids in a search for the capability to form aggregates of helices.109 Again, the hydrophobic collapse of the peptoids played the major role in the formation of those bundles. For this concept, every third side chain was a unit chosen from a pool of 12 different hydrophobic residues while the remaining monomer units were hydrophilic. The outer surface of the resulting amphiphilic helices exhibit hydrophobic and hydrophilic areas (approximately one-third to one-half). A fluorescence assay was used to mark hits (only about 3% of the prepared samples were considered a hit). Later, the same group continued this work by linking those helices covalently together.300 Förster resonance energy transfer (FRET) quenching, via attached fluorophores to each end of the peptoids, was used as detection of the desired hydrophobic collapse. Upon titration with several solvents, a cooperative disassembly was observed without destroying the helical structure. One step closer toward synthetic proteins was realized by this group by introducing a thiol and an imidazole moiety into a two-helix “bundle” as a zinc-binding site to resemble the function of a zinc finger (Figure 27).301 Variation of the position of those residues showed a huge effect on the zinc affinity, with apparent kd values differing by several orders of magnitude. Interestingly, the addition of zinc did not induce a perceptible effect on the helical peptoid structure and after the metal-bound was formed, the addition of acetonitrile did not lead to the unfolding of the structure. To complete these different hierarchical layers of molecular structures of peptoids, the final subsection will discuss quaternary structures. 3.4. Mimicking Quaternary Structures

We should clarify that from a biological point of view, one may note that quaternary structures are more or less exactly defined supramolecular assemblies of multiple folded proteins. However, we shall not be that strict in this Review and simply determine quaternary (poly)peptoid structures as supramolecular assemblies of multiple (poly)peptoid (macro)molecules in an ordered/hierarchical manner. In this definition, we excluded comparably unordered micellar structures from this section, as they have been discussed earlier, see section 2.5.1.2. 1779


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they combined a stepwise synthesis (SPPS) to generate the hydrophobic peptide block (six alternating repeats of leucine and 2-aminoisobutyric acid) with the NuLROP of sarcosineNCA to form the hydrophilic PSR block. Two different lengths of PSR were investigated, DP = 10 and 27. The polymer with the longer block resulted in very homogeneous nanotubes (Figure 30a). Upon adding the polymer with the shorter hydrophilic block, Y-junctions were formed. When polymers with identical composition but different chirality (from the leucine) were added, the tubes formed stereocomplexes upon heating and eventually merged into spherical assemblies.197 In further investigations, the same group gave evidence that the ratio of the length of the different blocks of different chirality have a major impact on the curvature of the formed nanotubes.196 Kimura et al. also used these amphiphilic polymers with opposite chirality to form nanoassemblies with shapes of roundbottom flasks upon heat treatment (Figure 30b).198,200 More recently, further structural elements were introduced. Two PSR chains and two histidine units were added to the previously used molecules. Together, all three building blocks are now able to connect, in a so-called “patchwork self-assembly technique”, the nanotubes with spherical structures to form stimuli-responsive Janus-type assemblies with the shape of stoppered round-bottom flasks (Figure 30c) stoppered flasks.308 Histidines as building blocks lead to pH sensitive aggregation behavior of the polymers. This was demonstrated to allow control over the assembly morphology, just by varying the solution pH, ranging from a twisted ribbon, over a helical ribbon, to nanotubes.309 3.4.4. Amylin-Like Structures, Microspheres, and Worm-Like Micelles. Peptoid structures that mimic amylin(20−29), which is associated with Alzheimer’s disease, Parkinson’s disease, and type II diabetes, have been synthesized by transforming a highly amyloidogenic peptide sequence into its corresponding peptoid and retro-peptoid sequence (Figure 31a).310 While the peptoid sequence did not form amyloid fibrils or any other secondary structures, the retro-peptoid sequence did assemble into supramolecular structures, comparable to ribbons or tapes, although not into amyloid fibrils. Moreover, the peptoid sequence was able to inhibit amyloid formation of native amylin(20−29) for at least 4 days. Servoss and co-workers used peptoids to form microspheres (diameter ∼0.3−3 μm) that could be interesting structures for applications in drug delivery or sensing (Figure 31b).311,312 Their methodical study showed the importance of the partial water solubility and helical content toward the formation of

capable of specific functions from linear, information-rich polymer chains. 3.4.2. Peptoid Superhelices. According to our definition of quaternary structures, superhelices or coiled-coils are other important motifs, which are present in proteins and nucleic acids (e.g., collagen fibrils). Such superhelices have also been generated via self-assembly of peptoids.307 Murnen et al. used the same monomer units that were utilized for sheet formation (as described above) but arranged those as diblock copeptoids rather than in an alternating sequence. Here, the peptoids were dissolved in the absence of peptoids with complementary charge. Interestingly, at first, sheet formation was observed upon dissolution in water at a concentration of 0.1 mM. However, after several days, superhelical structures with a diameter of 624 ± 69 nm and a length of up to 40 μm (Figure 29) were formed.

Figure 29. Atomic force microscopy scan of a superhelix formed from a sequence-specific 30-mer diblock with hydrophobic and anionic moieties (inset). Reprinted with permission from ref 37. Copyright 2013 Springer.

Once formed, they were stable in solution for months. Although the individual building blocks were achiral, the observed helices were homochiral. Different sequences did not result in any defined structures. Another essential condition for the successful formation of the superhelices is the optimal balance between charge repulsion and water solubility, which was found to be at 50−70% of deprotonated carboxylates. 3.4.3. Nanotubes and Round-Bottom Flasks. Selfassembly of amphiphilic polypeptoid-peptide hybrid block copolymers into discrete shapes was the topic in a series of papers by Kimura and co-workers.195 Synthetically interesting,

Figure 30. TEM images of (a) a mixture of the amphiphilic peptoid-peptide hybrid block copolymers, (b) round-bottom flask-shaped assembly prepared from the nanotubes and sheets with heat treatment. (c) Sealing of the flasks was achieved by adding planar sheet dispersion into the preprepared round-bottom flask to form dumbbell-type conjugate morphologies. Reprinted with permission from ref 195. Copyright 2008 WileyVCH. Reprinted with permission from ref 200 and 308. Copyright 2013 and 2015 Royal Society of Chemistry. 1780


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Figure 31. (a) TEM images of an aggregate of supramolecular ribbons and tapes of the retro-peptoid sequence. Reprinted with permission from ref 310. Copyright 2007 Elsevier Ltd. (b) SEM image of microspheres with a diameter of (3.2 ± 1.6) μm. Reprinted with permission from ref 311. Copyright 2013 Royal Society of Chemistry. (c) Cryo-TEM images obtained from dilute methanol solutions of the cyclic block copolypeptoid after 15 days. Reprinted with permission from ref 313. Copyright 2011 American Chemical Society.

microspheres.311 They could demonstrate that variation in a single residue could make the difference between the formation of well-defined microspheres and no assembly at all. Moreover, changing the side chains by means of bulkiness and placement of the charge had a huge impact on the size of the resulting microspheres. In additional work, they demonstrated the coating of glass and silicon substrates with these microspheres,312 which could be interesting for ligand presentation or to prevent fouling. While investigating the differences between cyclic and linear nonionic amphiphilic copolypeptoids (of PSR and Ndecylglycine), Zhang and co-workers found an interesting effect in their self-assembling behavior.313 To begin, spherical micelles formed in methanolic or aqueous solution/suspension. However, after a few days, both polymers eventually evolved into cylindrical (wormlike) micelles that exhibit a diameter of only a few nanometers but several micrometers in length (Figure 31c). The previous sections tried to show and discuss the versatility of (poly)peptoids as materials platform. The possibilities of stepwise synthesis and polymerization appear endless and a lot of potential remains untapped. However, numerous hierarchical structures and self-assemblies are already accessible, and we believe that even more complex and functional structures will soon be discovered, eventually maybe even engineered and designed. Since several authors indicate that one big goal is the preparation of (poly)peptoidbased synthetic enzymes and many building blocks mimicking protein structures are already available, we anticipate that the successful realization of this dream may be within reach.

4.1.1.1.1. Immunogenicity. First, hints toward the nonimmunogenicity of poly(sarcosine) (PSR) were given by Blout et al. as early as 1959.314 Later, in a series of papers which appear to have been largely forgotten, Moran and co-workers investigated PSR conjugates to allergens such as grass pollen extract.315−319 It was found that PSR-conjugation was suitable to suppress an immune response to an antigen after antigen conjugation. Intraperitoneal inoculation and subsequent intravenous injection with PSR conjugate led to a significant reduction in the IgE antibody response.315 It was noted that the immunosuppressant activity was not as pronounced for PSR conjugates as, for example, for PEG conjugates. However, the authors claim that the dose used for PSR conjugates was much lower. It is interesting to note that the PSR conjugates were very effective to suppress the induction of IgE response in mice. However, this effect was reportedly transient.316 In vitro studies on lymphocytes led the authors to speculate on a short-lived antigen-specific T cell suppression.317 Although it was argued that PSR conjugates were not performing well enough in the assays to warrant clinical development, interesting differences between PEGylated allergens and allergens conjugated to other water-soluble polymers [e.g., poly(D-glutamic acid-co-L-lysine)] were noted. Also, as a result of these studies, the authors hypothesized on a new modality for the treatment of allergies: continuous exposure to allergen to attenuate response to seasonal allergies.318 This treatment is now called allergen immunotherapy or hyposensitization. In the last communication of this series, the level of serum IgE was also followed in mice intranasally exposed to grass pollen.319 The mice were also treated with a conjugate of PSR to grass pollen. It was found that the conjugate completely prevented antibody formation, if the conjugate was coadministered from the beginning of the experiment. If the mice were primed with pollen and conjugate administration using the same route commenced after priming, the conjugate was still able to reduce the IgE titer. Moran and co-workers therefore called PSR a tolerogen. Kimura and co-workers investigated pharmacokinetics of PSR-containing block copolymers, apparently unaware of the studies of Moran and co-workers. Mediated by B-lymphocytes, so-called lactosomes [comprising poly(sarcosine)-block-poly(Llactic acid)] were rapidly cleared after repeated injection.320 Investigations using peptosomes (the hydrophobic block is made of an peptide) revealed a correlation between the high local density of PSR and the prevention of interaction with antibody B-cell receptors.321,322 The lactosomes act as T cellindependent antigens. Very recent investigations of Kimura and

4. APPLICATIONS OF (POLY)PEPTOIDS 4.1. (Poly)peptoids as Biomaterials

Due to the relation to (poly)peptides, (poly)peptoids have always been investigated in the context of biomaterials. Since supra- and macromolecular engineering is often used to prepare structures intended to use as biomaterials, we find it appropriate to review what has been done with (poly)peptoids as biomaterials. We have reviewed this topic a few years ago,39 but since then, a number of older papers came to our attention, which have been widely forgotten, and also new and important insights have been gained. 4.1.1. Biocompatibility and Degradability. 4.1.1.1. Biocompatibility of (Poly)peptoids. Minimizing adverse effects is a principal aim when using biomaterials. Therefore, high demands on polymers applied in medicine and healthcare are made. (Poly)peptoids are currently promising to meet these expectations, including biocompatibility and (bio)degradability. 1781


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Figure 32. Cell viability assays of various polypeptoids: poly(sarcosine) (P1), poly(sarcosine)-block-poly(N-n-propylglycine) (P3), poly(sarcosine)block-poly(N-n-ppentylglycine) (P6), and poly(sarcosine)-block-poly(N-n-propylglycine)-block-poly(sarcosine) (P11). Reprinted with permission from ref 324. Copyright 2014 Wiley-VCH.

onset temperatures close to or lower than 37 °C. As a result, significant cytotoxicity of these polymers was observed. 4.1.1.2. Degradability of (Poly)peptoids. N-Substitution of peptides is a common tool of biological and medicinal chemistry to enhance the resistance of sequences toward enzymatic degradation or to modify their conformation.1,325−327 However, a certain extent of biodegradation appears to be advantageous for the application of peptoids in pharmaceuticals, thus reducing the risk of accumulation with potentially negative implications. In this context, three different forms of degradation need to be considered: hydrolysis by acidic environments, proteolytic digestion by enzymes, and oxidative degradation by so-called reactive oxygen species (ROS). 4.1.1.2.1. Acidic Hydrolysis. Like (poly)peptides, watersoluble (poly)peptoids are prone to hydrolysis under highly acidic conditions (6 N HCl, pH −0.8, 120 °C), yielding the respective amino acids.249 However, as similar conditions are not met within mammalian tissue, acidic hydrolysis is considered to be not of relevance for the biodegradation of (poly)peptoids. 4.1.1.2.2. Digestion by Enzymes. As mentioned previously, the introduction of tertiary amide bonds is known to introduce excellent resistance to proteases. Studies by Zuckermann and co-workers indicate that enzymatic degradation of peptoids does not occur.328 The degradation of specifically designed peptide sequences consisting of L-amino acids was investigated using a number of important enzymes (carboxypeptidase A, papain, pepsin, trypsin, elastase, and chymotrypsin). This was compared with the degradation of the respective sequences of D-amino acids as well as peptoids and retro-peptoids in reverse order. As expected, chain scission of the L-amino acid sequences was observed. In contrast, neither D-amino acid sequences nor

co-workers revealed that high concentrations of lactosomeresponsive B1a cells are located in the peritoneal cavity of mice, from where they migrate into spleen tissue as a result of stimulation by lactosomes.323 4.1.1.1.2. Cytotoxicity. Despite the use of PSR in animal studies in various contexts, until recently, the cytotoxicity of PSR or other polypeptoids has not been investigated. Zhang et al. studied the cytotoxicity of cyclic random copolymers of Nethylglycine and N-butylglycine.71 Using the CellTiter Blue cell viability assay, incubation of human embryonic lung fibroblasts (HEL229) was performed in PBS buffer containing the copolymer in concentrations up to 5 g/L. After 24 h, a cell viability of approximately 80% was observed, comparable with PEG of similar molar mass. Recently, Luxenhofer and co-workers examined the cytotoxicity of PSR as well as different block copolymers consisting of sarcosine and N-propyl- or N-pentylglycine, respectively (Figure 32). Up to 10 g/L, depending on the solubility of the particular polymer, no cytotoxicity was observed.324 Cell viabilities (HepG2) were found above 80%, as determined using a WST-1 assay after 24 h of incubation. Ling and co-workers reported low cytotoxicity of copolymers obtained from sarcosine-NTA and N-butylglycine-NTA comparable with PEG and PSR.70 More detailed studies of the same group investigated the cytotoxicity of random copolymers comprising sarcosine and N-butylglycine units using a MTT cell viability assay.189 With dependence on the composition of the polymer, different onset cloud point temperatures resulted in concentration-dependent cytotoxicity. At low concentrations, up to 1 mg/L, samples dissolved in water at 37 °C and were noncytotoxic, comparable to PSR. Increased concentrations of 3 mg/L resulted in partial precipitation of the polymer with 1782


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Figure 33. Potential mechanism of oxidative (poly)peptoid degradation compared to the degradation of PEG (left) and of poly(2-ethyl-2-oxazoline) (right). Reprinted with permission from ref 341. Copyright 2014 Elsevier Ltd.

the formation of a gradient copolymer with a higher proportion of sarcosine at the N-terminus, it can be hypothesized that Proline Iminopeptidase cleaves N-terminal sarcosine as well. As this enzyme was found not only in bacteria and chicken egg white, but also in rat, rabbit, and swine tissue like liver, kidney, spleen, heart, lung, and testis,329−332 the enzymatic degradation of (poly)peptoids should not be completely ruled out yet. However, even if PSR may be degraded by enzymes, it should be obvious that any projection to other (poly)peptoids should be handled with extreme caution. 4.1.1.2.3. Oxidative Degradation. Although the pathway of oxidative degradation is often underrepresented in the considerations of biomaterials stability, it is a significant part in the metabolism of proteins and associated with various diseases like cancer, neurological disorders such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and schizophrenia as well as chronic fatigue syndrome, congestive heart failure, and the process of aging.333,334 PEG-based hydrogels cross-linked by oligo(L-proline) linkers were shown to be degraded by a system comprising hydrogen peroxide and cupric ions within 4 days.335 According to Sung and co-workers, this can be attributed to the degradation of oligo(L-proline). However, the resistance of PEG as a polyether against oxidative degradation should be questioned as well. Early works by McGary Jr. showed that PEG is highly susceptible to oxidation under similar conditions, thus being degraded within 2 days or less.336 At the same time, Textor and co-workers investigated the stability of structural isomers of

peptoid sequences were modified or degraded. On the one hand, this is easily comprehensible with regard to the tertiary structure of enzymes. Access to their active site is usually impeded by steric hindrance, thus creating high substrate specificity and probably preventing digestion of the altered sequence in this case. On the other hand, it is noteworthy that all investigated enzymes, except Papain, rule out peptide chain scission next to a proline residue. As proline is the only naturally occurring proteinogenic secondary amino acid, it appears that a priori these enzymes are not well-suited to investigate the digestion of (poly)peptoids. Instead, it remains to be elucidated if enzymes which do not exclude chain scission next to proline residues or are even specific to proline are capable of degrading (poly)peptoids. A promising candidate is an exopeptidase called Proline Iminopeptidase, which, according to early works of Katchalski, cleaves exclusively N-terminal L-proline.329,330 In order to prove this assumption, they investigated the degradation of different copolymers comprising L-proline and D-proline, hydroxyproline, glycine, or sarcosine, respectively.329 The amount of free Lproline after exhaustive digestion was determined using a colorimetric assay and compared with a calculation based on statistical considerations. In the case of D-proline and hydroxyproline, their calculation is in good agreement with the detected amount of released L-proline. However, when sarcosine was used as a comonomer, the actual amount of released L-proline is 4.4 times higher than predicted. Taking into account investigations on the copolymerization of sarcosine and proline by Fasman and Blout,249 who observed 1783


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Figure 34. Pharmacokinetic change during multiple intravenous administrations of Lactosome (50 μg/mouse, Lactosome diameter: 35 nm). (a−d) NIFR images of tumor-transplanted nude mice 5 and 24 h after intravenous injection of ICG-labeled lactosome (n = 3) demonstrating significant influence of lactosome preinjection. (e) Time schedule for NIRF imaging and lactosome administration. Reprinted with permission from ref 320. Copyright 2012 Elsevier B.V.

sarcosine and either lactic acid or leucine-aminoisobutyric acid (Leu-Aib)n oligomers. These form nanoscopic assemblies, of which the biodistribution was studied.347−350 Upon single injections, all systems exhibited stealth properties and long circulation. Interestingly, depending on the hydrophobic domain, significant changes of the pharmacokinetics could be observed after multiple injections (Figure 34).320 However, incorporation of any active pharmaceutical ingredient into these nanoassemblies remains to be demonstrated. More recently, Barz and co-workers have picked up and revisited poly(sarcosine)-polypeptide block copolymers.190,351−354 Heller et al. prepared an PSR-based alternative to the well-known nonviral vector poly(ethylene glycol)-blockpoly(L-lysine) (PLL). Block sizes were varied and cytotoxicity, and transfection efficiency were assessed.351 Also, preliminary studies were conducted with respect to targeting micelles based on poly(sarcosine)-block-poly(γ-benzyl-L-glutamate), end-functionalized with a mannose derivative. Cellular uptake in DC 2.4 and bone marrow derived dendritic cells could be significantly (by approximately 50%) decreased by blocking the mannose receptor or the clathrin-mediated endocytosis.353 Fetsch et al. provided a preliminary study on polypeptoid amphiphiles for drug delivery.324 Whether the resulting aggregates are useful for drug delivery remains to be established. To date, only model substances were successfully solubilized. However, the cytotoxicity profile is rather promising (see section 4.1.1.1.2). Independently, uniform peptoids have been investigated in the context of drug, protein, or gene delivery. Barron and coworkers investigated the pharmacological effects of attachment of sarcosine to a short peptide sequence (C20), an approach they termed NMEGylation (after N-methylglycine).355 While it was found that the stability and solubility were enhanced by attaching peptoid oligomers (up to 20 units of sarcosine), they found that attaching more than one sarcosine unit severely interfered with binding to the peptides target. In fact, to retain a reasonable biological activity, the C-terminus of the peptide was modified with glycine-sarcosine. Sequence-specific peptoids356 and lipid-peptoid conjugates357,358 (with regard to the term lipitoids, it should be

polypeptoids (i.e., poly(2-oxazoline)s), in comparison with PEG. Interestingly, poly(2-oxazoline)s were found to be much more stable than PEG.337−340 Inspired by these contradicting results, Luxenhofer and coworkers analyzed the degradation of PEG as well as poly(Nethylglycine) and poly(2-ethyl-2-oxazoline) in solution and depending on the concentration of the oxidative species.341 As expected, degradation depended strongly on the concentration of hydrogen peroxide (0.5−50 mM). Furthermore, it was shown that the degradation rate correlates with the degree of polymerization, as longer polymers chains were degraded faster than shorter ones, probably due to the influence of more readily oxidizable end groups (i.e., amines vs amides). In the case of shorter polymer chains, a greater proportion of end groups may decelerate oxidation of the polymer backbone and thus degradation of the polymer. However, this needs to be elucidated in more detail. Most importantly, at a similar degree of polymerization, PEG was shown to be less susceptible to oxidative damage than both pseudopolypeptides. Proposed mechanisms of oxidative degradation demonstrate the possibility of backbone scission for all three investigated polymers (Figure 33). Nevertheless, although Sung and coworkers stated the applied conditions as biologically relevant, it remains to be demonstrated how these results are applicable to in vivo conditions. 4.1.2. Drug Delivery. As in some other aspects of (poly)peptoids research, studies in the context of drug delivery were conducted for uniform as well as nonuniform (poly)peptoids. Both communities appear to be rather oblivious to each other. The earliest studies containing nonuniform polypeptoids, specifically PSR, for drug delivery came out of the group of Imanishi.342−346 Kimura later continued and extended these studies.201,320−322,347−350 So-called peptosomes, comprising PSR as hydrophilic moiety and poly(γ-methyl L-glutamate) as hydrophobic moiety, showed long blood circulation times comparable to PEGylated liposomes as well as enhanced accumulation within the model liver tumor tissue. In recent efforts, the Kimura group is concentrating their work on amphiphilic block copolymers of 1784


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Figure 35. Comparison of the pharmacokinetic profile of different antimicrobial peptide and peptoids. It was confirmed that peptoids exhibit higher stability in vivo; in addition, higher tissue accumulation and slower excretion was observed. Reprinted from ref 368. Copyright 2012 American Chemical Society.

demonstrated very early the potential of peptoids in supramolecular binding to relevant targets. A few years later, Kodadek and co-workers also used a library approach and identified potent transcription factor mimics.364 Besides ligands to modulate protein expression or biological signaling, some effort has been divested into development of antimicrobial peptoids.97,365−370 Scialdone and co-workers investigated β-peptoids with cationic and hydrophobic building blocks and found moderate activity against E. coli.97 In a series of papers, Barron and co-workers investigated antimicrobial peptoids, some of which show antibacterial activity at lower concentration than clinically employed antibiotics (Figure 35).365−368 Good antimicrobial activity coupled with low toxicity in mammalian cells could be achieved. Also here, the easy structural variation was valuable in the development. Another interesting application in which interaction with cell membranes is important are so-called cellpenetrating peptides, for which, of course, also the analogue cell-penetrating peptoids have been studied. Kodadek found that peptoids in general exhibit a better membrane permeability as compared to peptides.371 This is also true for the individual amino acids.372 Olsen and co-workers investigated hybrid structures of peptides and β-peptoids as cell-penetrating applications285 and for their antiplasmodial activity.284 Peréz-Payá, Vicent, and co-workers identified a peptoidinhibitor of the apoptotic protease-activating factor 1 (Apaf1)373,374 and also conjugated it to a poly(glutamic acid) as a carrier.375 This conjugate was able to reduce inflammation in renal tubular cells.376 Kodadek reported on what they call a peptoid-based “antibody surrogate”.377 Binding affinities and specificities similar to antibodies were achieved by peptoid dimerization. Liskamp310 and, more recently, Bezprozvanny and co-workers378 studied peptoids to inhibit amyloid aggregation, and Gilon91 and co-workers studied protein kinase B inhibitors. Barron and co-workers investigated biomimetic peptoid analogues of lung surfactant proteins.379,380 Other recent examples include autophagy enhancer381 and αmannosidase inhibitors.382

noted that the term lipitoid is not only used for lipid-peptoid conjugates but also used for other lipidlike materials)359 were investigated for gene delivery early in the development of the peptoid field. Using a combinatorial approach, Zuckermann and co-workers developed effective transfection agents. Interestingly, it was reported that simple analogies (same side chains) to, for example, PLL, did not work well. Rather a triplet motif of one cationic and two aromatic moieties was found to be particularly effective.356 In a similar approach, Zuckermann also screened for the transfection efficiency of lipitoids. Again, specific sequences, similar to the ones found in the above-mentioned study without the lipid component, were investigated. However, in this instance, the triplet motif comprised a cationic and two aromatic moieties substituted in para-position with a methoxy residue.357 Later, Lobo et al. tried to establish structure property relationships between the primary structure of the peptoids, the physicochemical properties of the polyplexes, and their transfection efficiency. Unfortunately, no clear deductions could be made.358 One could say that although these peptoids would seem ideal to deduce design principles, it appears to be not straightforward to do so successfully. Recently, lipitoids were successfully employed in bovine trophectoderm CT-1 cells. Significant improvement over other standard transfection protocols was reported.360 4.1.3. Pharmacologically Active (Poly)peptoids. Obviously, (poly)peptides are well-known to be often pharmacologically active. Considering (poly)peptoids are peptide mimetics with an excellent propensity for protease resistance, development of pharmacologically active (poly)peptoids appears immediately intriguing. Accordingly, the development of peptoid-based ligands binding to relevant receptors was among the first fields peptoids were applied. This topic was reviewed a few years back by Zuckermann and Kodadek361 as well as Blackwell and co-workers.362 Here, we will only discuss a few classic examples and some newer developments. Using a library of 5000 di- and tripeptoids, nanomolar ligands of G-protein coupled receptors were identified and tested pharmacologically in various species.108,363 This 1785


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Figure 36. Comparison of protein adsorption of different zwitterionic peptoids at different degrees of surface coverage. Clearly, the surface coverage must be higher for the shorter 20-mers as compared to the 36-mers. In comparison, the effects of the different structures of the peptoids are minor. Adapted with permission from ref 388. Copyright 2015 Wiley-VCH.

stem cells showed no adherence to PSR brushes irrespective of whether the surfaces were preincubated cell culture media or serum supplemented media (Figure 37).

Barron reported a strategy with which the authors hope to reduce the effort necessary to identify peptoid-based analoga of therapeutically active peptides by screening systematically peptoid-replaceable amino acids in the primary sequence.383 This approach is still somewhat labor-intensive. Ultimately, it would be very attractive if computational approaches to this problem became available. 4.1.4. Nonfouling Surface Coatings. In a series of papers, Messersmith and co-workers studied the nonfouling properties of peptoids grafted onto various surfaces.384−388 In all accounts, 3,4-dihydroxyphenylalanine (DOPA) derivatives were used to anchor the peptoids to the surfaces. Initially, oligomers of Nmethoxyethylglycine were studied and nonfouling properties were maintained for several months.384 Subsequently, other side chains were investigated and minor differences were observed.385,389 Also effects of surface coverage and degree of polymerizations were investigated. A minimum of 15 repeating units was found to elicit excellent and long-term (several months) nonfouling properties.386,387 All previously investigated peptoids were nonionic in nature. More recently, also peptoids with betaine containing side chains were investigated.388 The results of this work shows that surface grafting and chain length effects are dominant factors in determing the performance of these structures (Figure 36). Very recently, the first investigations on nonfouling surfaces obtained by surface-initiated polymerization of sarcosine-NCA were reported.151 The investigated brushes were approximately 20 nm thick, which would correspond to approximately 50mers, if the chains were fully extended. Incubation with fetal bovine serum (FBS) resulted in no detectable (by surface plasmon resonsance) adsorption. Also, human mesenchymal

4.2. Energy Materials

For more than a century, electricity has strongly affected human society, arguably as much as chemistry has. With the discussion on limited fossil resources and potential alternatives from renewable resources, better solutions toward energy storage have beecome of major issue in recent years. Lithium-ion polymer batteries (LiPo) include a polymer electrolyte instead of the more common liquid electrolyte and are promising due to the possibility of creating high-energy densities. Zuckermann and co-workers designed a series of uniform peptoids bearing ethylene oxide (EO)-based substituents via SPSS.390 The side chains consisted of 1 to 3 EO units and were chosen due to the high ion conductivity known from PEG-based materials (Figure 38). Synthesized polymers were characterized by analytical HPLC, MALDI-TOF-MS, DSC/TGA, and XRD. The glass transition temperatures (Tg) were found to decrease with increasing side chain length (see section 2.5.2.1). The i n t r o d u c t i o n o f l i t h i u m s a l t s (i .e ., l i t h i u m [ b i s (trifluoromethansulfonyl)imide]), causes an increase of the Tg, which also rises linearly with increasing salt concentration due to the complexation of the polypeptoid with these salts. Conductivity measurements at 50 and 90 °C clearly show that the highest ionic conductivity is achieved with the longest side chain, even though the conductivity was dependent on ion concentration and temperature. The highest conductivity (2.6 × 10−4 S/cm) was achieved at 100 °C and is higher than that of PEG-mimetic polypeptides. Nevertheless, the conductivity is 1786


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Figure 37. In situ SPR monitoring of protein adsorption from pure FBS on (a) native gold and (b) homogeneous PSR brush (d = 19.7 nm) on gold. (c) hMSC Cell adhesion on native gold (Au) PSR brush surfaces from pure culture medium (blue) and with an addition of 10% FBS (red), quantified by the LDH assay. (d) Fluorescence microscopy image of selected absorption of labeled albumin (Albumin-DyLight488) on a patterned PSR brush surface. The surface shows strong protein adsorption on areas of native gold but no adsorption on PSR covered areas (dots and stripes). Reprinted with permission from ref 151. Copyright 2015 Wiley VCH.

Figure 38. Change of glass transition temperature and Li+ coordination sites per chain in dependency of the side chain length. Reproduced from ref 390. Copyright 2012 American Chemical Society.

structurally analogous ethyleneoxy-containing diblock copolypeptoids poly(N-(2-ethyl)hexylglycine)-block-poly(N-2-(2-(2methoxyethoxy)ethoxy)ethylglycine) (pNeh-b-pNte) and poly(N-decylglycine)-block-poly(N-2-(2-(2-methoxyethoxy)ethoxy)ethylglycine) (pNdc-b-pNte) with 18 monomer units per block were investigated (Figure 39). By systematically studying the structure-conductivity relationships of the two diblock copolypeptoids, the authors unexpectedly obtained a

significantly lower than that of PEG homopolymers at the same salt concentration. Balsara and Zuckermann also studied the impact of side chain structure on crystallization behavior. Interestingly, the triethyleneoxy-containing peptoid is amorphous as homopolymer but will crystallize when coupled to a poly(N-decylglycine) block.391 On the basis of this, Balsara and Zuckermann investigated lithium ion transport in amorphous and crystalline domains of the same peptoid block.210 Two 1787


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vinylpyrrolidone) and poly(N-vinylcaprolactam). Interestingly, poly(N-propylglycine) of higher as well as lower molar mass presents higher T0 values. The KHI performance was found to correlate positively with the concentration.393 Also poly(β-peptoid)s were analyzed in this context. Reyes et al. investigated the KHI performance of homopolymers as well as of block and random copolymers. The former bearing short side chains, as methyl and ethyl, present poor activity. The authors suggest that these chains are not long enough to disrupt the intermolecular water structure to avoid preform clathrate formation and further interactions with initial hydrate clusters. Copolymers that additionally contain poly(N-propyl-β-alanine) exhibit a slightly decrease in T0 values. The random copolymer consisting of poly(N-ethyl-β-alanine-co-N-propyl-β-alanine) showed the best performance as KHI, with T0 values of 10.4 °C.397 Surprisingly, the same number of monomer units arranged as a block copolymer lead to a diminished effect. Overall, in comparison to the KHI performance of the closely related polypeptoids, the poly(β-peptoid)s show a significantly poorer performance. 4.3.2. Antifreeze Agents. The formation of ice is arguably among the pervasive natural crystallization processes. All the more, it is surprising that in many respects the freezing properties of water are not completely understood.398 Ward and Kirshenbaum investigated the ability of peptoids to control ice crystallization which would be useful in antifreeze agents.394 A small library of peptoids ranging from trimers to heptamers with side chains bearing hydroxyl, methoxyethyl, and methyl substituents was synthesized. For comparison, glycerol and short oligo(serine)s were used (Figure 40). Their impact on ice morphology was evaluated with variable temperature video microscopy. Crystals grown in the presence of any additive appeared smaller than those grown in pure water. However, the most significant reductions compared to the ice crystals grown in water (Figure 41) were observed for the tripeptoids, especially with the trimer of the hydroxylcontaining peptoid Ac(Nser) (Figure 41).

Figure 39. Different structures of poly(N-alkylglycine)-block-poly(N2-(2-(2-methoxyethoxy)ethoxy)ethylglycine) block copolymers. Reprinted from ref 210. Copyright 2014 American Chemical Society.

comparable intrinsic conductivity for the crystalline and amorphous pNte at the same salt concentration and temperature. However, the thermal properties are very different. 4.3. Crystallization Modifiers

Native biopolymers have the ability to precisely modulate the formation of inorganic crystalline materials.392 Despite their versatility and ease of structural modification, peptidomimetic oligomers or polymers like polypeptoids have not yet been explored extensively as crystallization modulators. Recently, (poly)peptoids have been applied to inhibit the formation of gas hydrates,393 to control the ice crystallization (antifreeze agents),394 and to control the crystallization of calcite (CaCO3).395,396 4.3.1. Kinetic Hydrate Inhibitors. Natural gas, besides crude oil and coal, is one of the big energy resources of our world. A serious problem for offshore as well as onshore oil and gas production plants is the accumulation of gas hydrates and their plugging of pipelines. Among other problem-solving approaches, the use of kinetic hydrate inhibitors (KHIs), which delay hydrate formation, is investigated by different research groups. Very recently, Kelland and Reyes studied the suitability of different polypeptoids and poly(β-peptoid)s for gas hydrate kinetic inhibition using a natural gas mixture to promote SII hydrates.393,397 Polypeptoids are potentially very suitable for this purpose because of the possibility of their backbone to form hydrogen bonds with water molecules and hydrophobic side chains featuring an affinity to gas hydrate cavities. The most important physicochemical properties are molecular weight, cloud point, and onset temperature of crystal growth (T0). The latter was determined by a series of constant cooling experiments which were carried out in high-pressure rocking cells. For polypeptoids, Kelland et al. showed that certain adaptations to the alkyl carbon chain attached to the polymer increase kinetic hydrate inhibition as long as water solubility is maintained. The best result was given by poly(N-propylglycine) (Mn = 2.2 kg/mol) with an average T0 value of 4.7 °C, which compares favorably with established KHIs such as poly(N-

Figure 41. Ice crystals grown at −1.0 °C in (a) pure water or (b) 10 mg/mL Ac(Nser)3 aqueous solution. Reprinted with permission from ref 394. Copyright 2012 National Academy of Sciences.

Furthermore, the ice crystal growth rates were investigated by measuring the advance of the ice growth front over time.

Figure 40. Peptoids and peptides with varying sequence lengths (n) investigated as antifreeze agents.394 1788


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of 50 nM and nearly 28-fold at 200 nM. If the concentration was increased further, the step speed diminished significantly, possibly due to surface binding. As an explanation for the growth acceleration, the authors established three hypotheses. The first is that peptoids effectively increase the local concentration. Also, it is suggested that due to coordination, the energy barrier of desolvation and/or orientation is lowered. As the third mechanism, the authors propose that the water layer adsorbed to the crystal surface is disrupted, decreasing the energetic cost of removing water from the crystal surface. Recently, DeYoreo, Zuckermann, and co-workers extended this work by synthesizing 28 different peptoid chains and studying the peptoid-induced controls over calcite morphology in a more systematic evaluation.396 It has been demonstrated that the morphology as well as the acceleration or inhibition observed during the growth of calcite can be adjusted by balancing the electrostatic and hydrophobic interactions. The dominant role can be assigned to the latter. Interestingly, either strong hydrophobic or electrostatic interactions inhibit crystal growth and reduce expression of the (104) face. In conclusion, the authors hypothesize a model for peptoid interaction with the calcite (Figure 43). In this configuration the polar groups are designed to bring the hydrophobic groups close to the surface, where they act to disrupt the adsorbed water layer. This supports the third hypothesis (vide supra). Due to the large number of primary amines available for the synthesis of peptoid side chains, the authors suggest that the variability for designing peptoids that are useful at controlling crystallization is broader than that available through synthetic proteins.

The slowest rates were observed in the presence of peptoid trimers and hexamers, regardless of the side chain identity. Surprisingly, the usage of peptoid tetra- and pentamers results in even faster growth rates with respect to pure water. Additionally, the influence of the trimer additives on the melting temperatures of ice was studied by DSC. All additives depressed the melting temperature and only slight differences could be observed, with the exception of oligo(sarcosine) which had a smaller effect. However, the observed reduction in melting temperatures was significantly higher than the calculated values from colligative effects alone. Again the hydroxyl-containing peptoid exhibited the largest temperature shift relative to the expected colligative effect. Obviously, the short achiral peptoids used in this study do not exhibit conformational order. However, the authors suggest that peptoids which form secondary structures, as discussed in section 3.2, may further influence ice crystallization because of epitaxial matching with the crystal planes. This assumption is further supported by the studies of Davies and co-workers demonstrating higher activity of antifreeze proteins exhibiting a β-helix structures.399 4.3.3. Controlling Biomineralization. In nature, nucleation and growth of inorganic minerals like calcium carbonate are precisely controlled by peptides and proteins (biomineralization). This process consumes carbon dioxide, which offers the possibility to mimic the action of these natural biopolymers and develop a technology that is broadly applicable to industrial crystallization, including carbon dioxide sequestration. DeYoreo, Zuckermann, and co-workers designed different amphiphilic peptoids that fulfill the requirements, like the specific amino acid sequence, the number of carboxylic acid groups, and the overall hydrophilicity. These factors play an important role in the nucleation and growth of CaCO3 minerals.395 An analysis of the morphology of crystals grown in the presence of these peptoids revealed structures very comparable to those grown in the presence of native proteins. Moreover, other peptoids lead to CaCO3 crystals that exhibited a number of unique morphologies ranging from twisted paddles to spheres (Figure 42).

4.4. Chromatography Materials

Especially in the field of natural products chemistry, chromatography provides a useful analytical and preparative tool for the separation of mixtures of compounds and enantiomers. Due to the great variety of available chiral submonomers as well as the ability to form secondary structures, peptoids appear to be a useful platform for chromatography materials. For this purpose, Liang et al. investigated the application of peptoids in chromatographic processes.400−405 First studies demonstrated strong dependency of enantioseparation efficacy on the peptoid chain length, which was attributed to the formation of helical secondary structures.400 Although hydrogen bonds appear to have major impact on the separation of racemic mixtures, steric hindrance and π−π-interactions are considered to affect chiral recognition as well. Furthermore, chiral and achiral terminal groups can be introduced in order to optimize interactions between the peptoid chiral stationary phase (CSP) and the analyte.401−403 As demonstrated recently, quinine and quinidine moieties attached to the carbamate group in the C9-position further improve the performance of peptoid CSPs and even outperformed commercially available systems.405 Thus, applicability of peptoids as chromatography material is supported by their great potential for analyte-specific tuning.

Figure 42. Different morphologies. (a) “Twisted paddles” vs (b) spheres of CaCO3 crystals grown in the presence of diblock peptoids of N-(2-carboxyethyl)glycine (Nce) and N-(2-(X-phenylethyl))glycine (NXpe). (a) Nce12-block-NXpe4 (X = 4-chloro) and (b) Nce8-blockNXpe4 (X = 2,4-dichloro). Reprinted from ref 395. Copyright 2011 American Chemical Society.

4.5. Phase Transfer Catalyst and Ion Binding Peptoids

Interestingly, combinatorial peptoid libraries, which were discussed in section 2.2.3, are not only used in the light of biology or industrial drug discovery. Kirshenbaum and coworkers investigated metal-binding peptoids that form complexes with Cu(II) and Co(II).406 A hexa- and a pentamer with terminal hydroxyquinoline ligands were synthesized, and the resulting peptoid−metal complexes characterized using

Further investigations of the influence of the hydrophobic units as well as of the number of carboxylic acid groups clearly showed the significant tunability in the crystal morphology. Additionally, the dependence of the molecular step speed on the peptoid concentration was measured using in situ atomic force microscopy (AFM). It was established that the rate of crystal growth is increased by nearly 23-fold at a concentration 1789


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Figure 43. A model for the interaction between diblock-like peptoids and the calcite (104) face. Hydrophobic regions are represented in gray and hydrophilic regions in blue. Reprinted with permission from ref 396. Copyright 2014 Macmillan Publishers Limited.

Figure 44. Microscope images of TentaGel resin beads loaded with different peptoids after incubation in nickel solution and exposure to 1% dimethylglyoxime solution. A color change to red within the bead matrix indicates binding to nickel. Clockwise from left: PentA, NonaB, ConTG, and ConC. Adapted with permission from ref 409. Copyright John Wiley & Sons 2014.

workers as they identified sequences that can bind to Cr6+ in different environments.410 Almost always, the chosen ligands reduced the metal ion concentration to values close to the EPA limit for drinking water, 2 μM. Even a huge excess of competing ions like chloride or sodium, typical for ocean water, lead to an only slightly decreased efficacy.

titrations monitored with UV−vis and CD spectroscopy. Not surprisingly, investigations of cyclic peptoids that coordinate metal ions as well as the establishment of combinatorial assays were the next steps of this development. To date, only Na+ and Gd3+ were found to be coordinated by cyclic peptoids.211,407 However, Ca2+ complexation and transport through a lipid membrane was reported for cyclic octa(peptide-peptoid) hybrids, comprising sarcosine, lysine, and leucine, by Kimura and co-workers.408 OBOC peptoid libraries with selective affinity for particular metal ions in a heterogeneous mixture were created by Nalband et al.409 By using X-ray fluorescence, it was possible to screen the library of peptoid oligomers rapidly on solid support. Interestingly, only two compounds, PentA and NonaB, bound to Ni2+ ions, which is indicated by a red color change (Figure 44). Thus, it was possible to identify ligands that are able to remove specific ions from a buffered solution. Additionally, the authors pointed out that any atom with an atomic number larger than 12 can be monitored. The great value of the peptoid-based library was shown by Francis and co-

5. SUMMARY AND OUTLOOK: THE FRONTIER Although some (poly)peptoids have been known for a very long time, they have been in the shadows of polypeptides, their much more prominent brethren. Over many decades, poly(sarcosine), the most simple polypeptoid was virtually the only polypeptoid investigated and obtained through polymerization. The interest in this polymer was mainly due to the fact that side reactions, which hampered the controlled synthesis of synthetic polypeptides for decades, were presumed to be absent in the polymerization of the N-substituted N-carboxyanhydrides. At the same time, the polymer was interesting as it did not form secondary structures and exhibits low immunogenicity. Other 1790


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Biographies

polypeptoids were hardly investigated, presumably due to synthetic challenges. In the past few years, great progress was made in extending the toolbox for polypeptoids. Smart polypeptoids and multiblock copolymers were prepared, which will extend the application profile drastically. With the development of solid-phase supported and sequence-specific peptoid synthesis by Zuckermann and coworkers, a surge in interest in these biomimetic materials was initiated, which was entirely decoupled (and largely remains decoupled) from their nonuniform analogues. While uniform peptoid-peptide hybrids are well-established, interest in nonuniform hybrids was very limited but has become more intense recently. In contrast, the combination of nonuniform polypeptoids and polypeptides with uniform peptoids and peptides has hardly been touched upon. However, the results by Kimura and co-workers discussed in the review are very intriguing. With the development and refinement of the solid-phase peptoid polymerization (SP3), this combination becomes straightforward accessible. Accordingly, we see a lot of potential for future development in macro- and supramolecular engineering, biomaterials design, and biomimetic materials. Early work and more recent work clearly bring hope that (poly)peptoids can be tailored to exhibit an excellent biocompatibility profile. We expect that this will kickstart considerable work of (poly)peptoids in the field of nanomedicine. Biomimetic structures were realized with great success using peptoids, so it will be interesting whether polypeptoids or the combination of peptoids and polypeptoids will have a significant impact in this context. In the past few years, a new buzz-word, information rich polymers, has created some interest. Of course this is conceptually closely related to sequence specificity for which the use of peptoids and polypeptoids is a natural ally. Overall, the research in peptoids has matured in a very fascinating way and plays a crucial role in current supra- and macromolecular engineering. Polypeptoids are still in there infancy in many ways, but the promise can be clearly seen. The idea to combine peptoids and polypeptoids is just being conceived. We have no doubt that a bright, complex, and fascinating future lies ahead for (poly)peptoids.

Niklas Gangloff (pictured 2nd from left) received his B.Sc. in Chemistry from the Technical University (TU) of Dresden while conducting cell viability studies of different cell lines when incubated with an anticancer drug. In the course of his Master’s studies, he worked on biodegradable nanogel star polymers at the IBM Almaden Research Center in San José, California, and received his M.Sc. from the TU developing the solid-phase peptoid polymerization (SP3). Since 2013, he has been working on his Ph.D. at the University of Würzburg. In collaboration with Ronald Zuckermann at the Lawrence Berkeley National Laboratory, he is investigating polypeptoids and their aggregation behavior. Juliane Ulbricht (pictured 3rd from left) studied chemistry at the TU Dresden, Germany, and received her MSc. in 2013 for her Master’s thesis on the oxidative degradation of pseudopolypeptides. In 2014, she joined the group of Robert Luxenhofer at Würzburg University as a Ph.D. student. Her current research interests include the degradation behavior of polypeptoids by oxidative species as well as enzymes. Thomas Lorson (pictured far right) received his B.Sc. and M.Sc. in Functional Materials from the Julius-Maximilians-University in Würzburg, Germany. Under the guidance of Prof. Gerhard Sextl, he completed his thesis at the Fraunhofer ISC in developing preceramic polymers for the production of fibers. He joined the group of Robert Luxenhofer as a Ph.D. candidate in 2014. His current research focuses on the development of novel polymeric biomaterials and scaffold designs for tissue engineering applications.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

Helmut Schlaad studied chemistry at the University of Mainz, Germany, and earned a doctoral degree in Physical Chemistry, under Axel H. E. Müller in 1997. After one year of postdoctoral fellowship with Rudolf Faust at the University of Massachusetts in Lowell, USA, he moved to the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany. He finished habilitation, mentored by Prof. Markus Antonietti, and received the venia legendi in Physical

Author Contributions §

J.U. and T.L. contributed equally.

Notes

The authors declare no competing financial interest. 1791


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Chemistry in 2004. He was senior scientist at the Max Planck Institute of Colloids and Interfaces until 2014 and then moved to the University of Potsdam as a professor for polymer chemistry. His research interests are directed toward polymer synthesis, smart functional materials, and bioinspired polymer structures. Robert Luxenhofer (pictured left) studied chemistry at the TU München, Germany, and Sydney University, Australia. In 2007, he received his Ph.D. in polymer chemistry under the supervision of Rainer Jordan. Under the guidance of Alexander (Sasha) Kabanov, he conducted postdoctoral research in the field of nanomedicine and drug delivery at the University of Nebraska Medical Center in Omaha, Nebraska. In 2009, he returned to Germany as a KAUST Research Fellow and started to work on polypeptoids at the TU Dresden. Since 2012, he has been a professor for functional polymer materials at the Julius-Maximilians University Würzburg. His research interests include polypeptoids and poly(2-oxazoline)s, multicomponent reactions, nanomedicine and regenerative medicine, interaction of polymers with biological systems, and the questions of what we define as reproducibility in polymer science.

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