Orally Absorbed Cyclic Peptides - Chemical Reviews (ACS Publications)

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Orally Absorbed Cyclic Peptides Daniel S. Nielsen,†,‡ Nicholas E. Shepherd,†,‡ Weijun Xu,†,‡ Andrew J. Lucke,†,§ Martin J. Stoermer,*,† and David P. Fairlie*,†,‡ †

Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia ABSTRACT: Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol−water partitioning, hydrogen bond donors/ acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.

CONTENTS 1. Introduction 1.1. Absorption 1.2. Predicting Absorption 1.3. Metabolism 1.4. Oral Bioavailability versus Oral Activity 1.5. Formulation and Pharmacokinetics 1.6. Review Scope 2. Cyclic Tetrapeptides 2.1. CJ-15208 2.2. Apicidin and Chlamydocin 2.3. Beauveriolides 2.4. HIV Fusion Inhibitors 3. Cyclic Pentapeptides 3.1. DMP-728 3.2. Cyclochlorotine and Astin C 3.3. BL3020-1 3.4. Romidepsin 3.5. Largazole 3.6. Complement C5aR Antagonists 3.7. Actinomycin D 3.8. Leucine Cyclic Peptides 4. Cyclic Hexapeptides 4.1. Desmopressin 4.2. Melanotan II 4.3. Oxytocin 4.4. Anidulafungin, Caspofungin, and Micafungin 4.5. Somatostatin, Octreotide, and Analogues 4.6. Beauvericin and Enniatins © 2017 American Chemical Society

4.7. Nepadutant 4.8. Bouvardin 4.9. Pristinamycin and Related Antibiotics 4.10. 1-NMe3 and Related Cyclic Hexapeptides 4.11. Cyclo-[Arg-Arg-Arg-Arg-NaphthylAla-Phe] 4.12. Kahalalide F 5. Cyclic Heptapeptides 5.1. Sanguinamide A and Danamides 5.2. Rhizonin A 5.3. Microcystin LR 5.4. YM254890 5.5. CHEC-7 5.6. Polymyxin B1 and B2 5.7. Bacitracin A 6. Cyclic Octapeptides 6.1. PF1022A and Emodepside 6.2. WH1Fungin 6.3. α-Amanitin 6.4. Griselimycin and Synthetic Derivatives 6.5. Dihydromycoplanecin and Mycoplanecin 7. Cyclic Nona- and Deca-Peptides 7.1. CHEC-9 7.2. AFPep 7.3. Antamanide and Cyclolinopeptide 7.4. Cyclopeptolide 1 7.5. Permetin A 7.6. Synthetic N-Methyl β-Strand Decapeptides

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Received: December 20, 2016 Published: May 25, 2017 8094

DOI: 10.1021/acs.chemrev.6b00838 Chem. Rev. 2017, 117, 8094−8128

Chemical Reviews 7.7. Surotomycin 8. Cyclic Undecapeptides 8.1. Cyclosporin A and Synthetic Derivatives 8.2. THR-123 9. Cyclic Dodeca- and Tridecapeptides 9.1. Cerulide 9.2. L-Phenylalanine-Dipicolinate Macrocycle 10. Cyclic Tetradecapeptides and Beyond 10.1. Conotoxins and Synthetic Derivatives 10.2. Duramycin 10.3. Kalata B1 and Other Cyclotides 10.4. Stapled α-Helix 11. Influences on Oral Bioavailability 12. Conclusions and Future Prospects Author Information Corresponding Author ORCID Present Address Notes Biographies Acknowledgments Abbreviations References

Review

antibodies.18−20 They all need to be given by injection, with few peptides known to be orally absorbed and hardly any being truly orally bioavailable. There is now growing interest in developing molecules with molecular weights between those of conventional drugs and antibodies.18 Here we describe some examples of orally absorbed peptides, all being cyclic peptides of 4−37 amino acid residues.

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1.1. Absorption

When a drug is administered by oral, buccal, sublingual, nasal, dermal, intramuscular, subcutaneous, pulmonary, and rectal routes, it must be absorbed to enter the bloodstream where it is systemically circulated, distributed into tissues, metabolized, cleared, and excreted. Absorption is the process by which a drug moves unchanged from the site of administration to the site of measurement in the organism.21 Absorption from the gastrointestinal (GI) tract after oral administration occurs mainly from the small intestine. Small finger-like folds (villi) coating its surface generate a much larger surface area (200 m2) for compound absorption compared to the stomach (1 m2).21 The small intestine environment (pH 6−7.5) aids absorption because many molecules are uncharged at this pH and can passively diffuse through intestinal membranes. Passive diffusion is the most common way drugs and many nutrients are absorbed from the GI tract into plasma. Passive diffusion of drugs is most commonly transcellular (through cell membranes, > 90% of drugs) rather than paracellular (through tight junctions between enterocytes, 5−10% of drugs). Charged and hydrophilic molecules such as peptides are not well absorbed via passive diffusion mechanisms. Membrane-bound transporter proteins also mediate absorption of amino acids, very small peptides, nucleosides, sugars, ions and hydrophilic molecules via facilitated diffusion and active transport.22−26 Studies on peptide and protein transport across gastrointestinal mucosal membranes is still in relative infancy, understanding still confined mainly to single amino acids and small peptides and the biotin, transferrin, and glucose transporters. The human intestinal peptide transporter SLC15A1 is one example of a proton-dependent protein that transports very small peptides (2−4 residues) via facilitated diffusion.27 SLC15A1 also facilitates absorption of certain peptide mimetics and peptidelike drugs such as ACE inhibitors and β-lactam antibiotics.28 Conversely, some transporters in enterocytes (e.g., Pglycoproteins) act as a barrier to absorption,29,30 actively expelling peptides and drugs31 back into the GI tract.

1. INTRODUCTION Proteins and peptides are the largest group of naturally occurring mediators of biological and cellular processes, ranging in size from small peptide hormones to large multidomain polypeptides and proteins.1 Proteins bind with high specificity and potency irrespective of whether interactions are localized to one or more small binding pockets (“hot spots”)2−4 or more dispersed across larger surface areas. When protein function is localized, protein−protein interactions (PPIs) can potentially be interfered with by small drug-like molecules.5 However, more often than not the bioactive protein interfaces span large surfaces and rely upon multiple weak contacts for affinity and selective recognition. In these cases, an alternative approach to modulating PPIs is to mimic one of the interacting protein surfaces by downsizing it to smaller peptides or peptidomimetics. These are larger than small molecule drugs, frequently require molecular constraints to stabilize structure in water, and are usually not orally bioavailable.6−13 During the last 20 years the pharmaceutical industry has almost universally adopted drug-like property filters, such as the “rule-of-five” (RO5)14−16 and related parameters.17 These have guided the design and development of orally bioavailable modulators of macromolecules, deliberately focusing attention on small molecules restricted to MW < 500. In the era of postgenomics, transcriptomics, and proteomics, it is time to focus more attention on larger modulators of proteins that can span larger surfaces, access new therapeutic mechanisms of action, and provide greater target specificity.18 This has been spectacularly demonstrated by antibodies and some proteins that have spearheaded a paradigm shift in the pharmaceutical industry toward larger therapeutic molecules.19 Proteins and polypeptides are expensive to manufacture, chemically unstable (degraded by pH, heat, oxidation, and proteases), difficult to store, very flexible in water, immunogenic, have low membrane permeability, and poor oral bioavailability. Despite these limitations, many peptides and polypeptides are in clinical trials and a few are registered drugs, mainly naturally occurring peptides, their semisynthetic derivatives, cyclic peptides, or

1.2. Predicting Absorption

Predicting oral absorption of drugs in animals is complex and experimental measurements are low throughput. Attempts have been made to develop in vitro or ex vivo methods to assess membrane permeability. Although no in vitro or ex vivo model correlates well with in vivo parameters, some methods have allowed estimates of relative passive membrane permeability. However, others factors (membrane uptake via endocytosis, transporter proteins, protein-binding, stability to proteolytic and oxidative/reductive enzymes in the gut, intestine, tissues, plasma and liver, clearance rate and first pass metabolism) also contribute to oral bioavailability. The parallel artificial membrane permeability assay (PAMPA)32 has been used widely in drug discovery as a high throughput assay to estimate passive diffusion across a membrane. The artificial membrane lacks transporter proteins and so only estimates permeability via passive diffusion. 8095


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flavin-containing monooxygenases, monoamine oxidases and NADPH−CYP450 oxidoreductases. At this stage the compound can be (1) reabsorbed back into the bloodstream, sometimes unchanged; (2) metabolized and then absorbed into the bloodstream; or (3) combined with bile salts and excreted back into the GI tract. Metabolism of peptides can occur at all stages, while traversing the GI tract, in intestinal tissues, in the bloodstream, in the liver, and other organs and tissues. Peptides can be hydrolyzed by a myriad of proteases in the gut, plasma, and cells, for example, pepsin and HCl in the stomach; trypsin, chymotrypsin, elastase, and carboxypeptidases in the small intestine; and, by thrombin, plasmin and clotting factors in blood plasma degrade peptides. The CYP450 monooxygenases and oxidoreductases in the intestinal lining and in the liver catalyze carbon hydroxylation and epoxidation, heteroatom oxygenation and release. CYP450 enzymes account for > 75% of drug metabolism within the liver.56 Substances with good gut absorption can still have low oral bioavailability if metabolism in the intestinal lining, liver, plasma, or elsewhere is high, or clearance is rapid. It is a misconception that high gut permeability equates to high oral bioavailability. Stability to metabolic enzymes, especially in the gut, liver, and blood, is important when predicting oral activity of membranepermeable compounds. Finally, a relatively new consideration is the influence of the microbiome on drug and nutrient metabolism. Differences in oral bioavailability between people or animals are often attributed to differences in metabolic enzymes or their efficiencies that change with age, genetics and environment. Until now, the influences of symbiotic bacteria inhabiting the gut on oral drug stability, metabolism and absorption have not been considered much and this is likely to be important to study in the future.

Caco-2 cells are heterogeneous human epithelial colorectal adenocarcinoma cells grown under conditions to mimic absorptive cells of the small intestine.33 Their microvilli, metabolic enzymes (e.g., peptidases and esterases), transporter proteins, and bile salts better mimic the physiological environment.34 PAMPA and Caco-2 assays can indicate whether a compound is passively or actively transported across epithelial cells. Madin-Darby canine kidney (MDCK) cells isolated from dog kidney cortex35 retain many properties of the kidney tubular epithelium. Morphologically, MDCK cells exhibit apical microvilli, junctional complexes, and lateral membrane infoldings36−39 characteristic of transporting epithelia.40 Physiologically, MDCK cells transport sodium and water in an apical-to-basal direction. When grown on permeable substrates, MDCK cells generate transepithelial electrical resistance indicating functioning tight junctions.41 These properties resemble Caco-2 cell and other intestinal tract cells, making MDCK cells a viable model for measuring in vitro permeability despite their anatomical origin. Like Caco-2, MDCK cells have uptake and efflux transporter-proteins, but their canine origin may endow different affinity, selectivity, and activity for substrates compared to human proteins and cells. Therefore, caution should be exercised in interpreting these results.42 MDCK monolayers are faster to culture (3−7 days)43 than Caco-2 (14−28 days), making them useful for high throughput permeability assays. A derived cell line, MDCKIILE (low efflux) was developed from subpopulations of MDCK cells.44 MDCKII-LE have greatly reduced expression of canine mRNA/protein and low active uptake/efflux properties making them a live cell alternative to the artificial PAMPA assay. There have been many recent reviews of cell and membrane permeability of cyclic peptides and other macrocycles,45−50 so we will not be covering that literature here. While this is of importance, it is not the only contributor to oral absorption and oral bioavailability. Many membrane and cell permeable compounds show negligible oral bioavailability. Instead of measuring transport in vitro across cells, an Ussing chamber51 can be used to estimate oral absorption by measuring ex vivo membrane transport of ions, nutrients, and drugs across mouse52,53 or rat54,55 intestinal tissue. However, such experiments also correlate poorly with oral bioavailability (F%) in rodents and humans. Thus, the Ussing chamber has become less popular in industry over the past decade.

1.4. Oral Bioavailability versus Oral Activity

Oral bioavailability (F) is the fraction of an orally administered compound that reaches the systemic circulation intact. Absorption alone is not a good predictor of oral bioavailability, since extensive first-pass effects in the liver and intestine can lead to poor systemic exposure. Thus, blood is usually sampled from the jugular, rather than portal, vein to take into account first pass metabolism. Oral bioavailability is defined as the ratio of the amounts of drug found in plasma after intravenous (iv) versus per oral (p.o.) dosing, with the iv dose representing 100% bioavailability.21

1.3. Metabolism

Orally administered compounds face many obstacles en route to the plasma. Compounds of high molecular weight, high lipophilicity or low solubility are recognized and degraded by metabolic enzymes. Orally ingested compounds are first exposed to digestive amylases in the saliva, where glycosidic bonds of starch and other carbohydrates are hydrolyzed. Then in the stomach, acidic (pH 1−2) gastric juice containing peptidases begins to degrade proteins and other nutrients. Upon entering the duodenum, the pancreas excretes additional enzymes (proteases, lipases, amylases), bile salts and pHneutralizing bicarbonate. Next, in the jejunum and ileum (small intestine) the pH is 6−7.5 and most processed nutrients and drugs are absorbed here. Intestinal P450 enzymes can metabolize compounds even before they enter the bloodstream and thus reduce measurable oral absorption. Once absorbed from the GI tract, compounds enter the hepatic portal vein, flow into the liver and are perfused into hepatocytes for firstpass metabolism by cytochrome P450 (CYP450) enzymes and

F(%) = 100 ×

AUCpo dose po

×

dose iv AUCiv

For clinical trials, drugs normally need to have F > 20%. Other parameters described in this review that relate to oral bioavailability include the following: the area under the curve (AUC), used to express the cumulative amount of drug found in plasma over a period of time; the clearance rate (CL), the volume of plasma from which a drug is completely removed per unit time; the peak serum concentration (Cmax), the time to reach peak serum concentration (Tmax); the half-life (t1/2), time taken for serum drug concentration to decrease by half its original amount; and the volume of distribution (VD), the apparent volume in which the drug is distributed at steady state. These parameters provide quantitative estimates of the compound absorbed and surviving first pass metabolism. 8096


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rats. Pharmacokinetic investigations in rats often involve sampling blood at multiple time points from the same animal through a surgically implanted line. This is more difficult for mice, for which studies usually involve larger groups of animals, so that multiple mice can be sacrificed at each time point. Pharmacokinetic parameters measured by the latter method provide less accurate results due to variation within animals (metabolism, total blood, body volume, individual weight, etc.) or their environments. It is therefore prudent to carefully consider parameters such as dose, species of test animal, and experimental design before drawing conclusions.

Oral activity is often used as a surrogate to infer oral bioavailability. Orally dosing an animal and observing a therapeutic effect provides only qualitative evidence of oral bioavailability. We have included reports for orally active peptides in this review even though many such molecules are poorly absorbed; most peptides and proteins are < 1% orally bioavailable. We urge caution in drawing robust conclusions about oral bioavailability of molecules from such studies. The observed biological effect could occur by indirect mechanisms, from metabolites or may be due to exceptional potency of trace material absorbed. The main measures of oral activity used in this review are the oral dose (mg/kg p.o.) required to induce a measurable response; the effective dose for 50% of the maximal response (ED50); and the lethal oral dose required to kill 50% or 100% of the test population (LD50 and LD100).

1.6. Review Scope

Most proteins and peptides show negligible oral bioavailability (F < 1% and usually F < 0.1%). Very few peptides are sufficiently orally absorbed to produce some physiological effect in an animal. Cyclic peptides are the most orally bioavailable peptides known, but only a handful show F ≥ 10%. Other types of macrocycles are orally absorbed, but the reader is directed to other reviews for these.64−67 This review covers only orally absorbed cyclic peptides reported up until 2016, including some that are absorbed in only trace amounts but sufficient to induce a physiological response. Cyclic peptides have been classified herein according to the number of residues in their macrocyclic portion. For some highly modified cyclic peptide natural products, we have grouped them with cyclic peptides of equivalent macrocycle size (e.g., largazole is grouped with romidepsin). In cases where a related series of different sized cyclic peptides were developed for the same target, we have grouped them together based on the smallest cyclic peptide in the series in order to streamline discussion and avoid repetition. The main focus of this review is on cyclic peptides larger than four residues because they violate most, often all, rule-of-five (RO5)14−16 and associated17 parameters. We have also included a few representative cyclic tetrapeptides, even though these usually comply with RO5 parameters. We describe 125 cyclic peptides in total for which there is evidence of oral absorption, oral activity, or oral bioavailability. Where possible, we have indicated relevant doses, formulations, pharmacokinetic parameters, and pharmacological activities. In some cases, there was evidence of solid state or solution conformations that indicated rigidity or flexibility that likely influence absorption. These are referenced to codes in the Protein Data Bank (PDB) or Cambridge Crystallographic Data Centre (CCDC). Our review concludes with an analysis of this compound set for influences of physicochemical parameters normally considered to affect oral bioavailability. A recent review68 on bioactive linear and cyclic peptides from the ChEMBL database only examined eight cyclic peptides that were orally administered. For the cyclic peptides that follow, we have calculated molecular weight (MW), the predicted octanol− water partition coefficient (Molinspiration LogP, miLogP), the number of hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA) as strictly defined by Lipinski and colleagues, the number of rotatable bonds (RotB), and the topological polar surface area (tPSA), all determined with the aid of the Molinspiration webportal (http://www.molinspiration.com).69 We plot each of these six parameters against oral bioavailability (F%), for those compounds where oral bioavailability has been reported. We then discuss how the findings relate to the RO5 and associated guidelines commonly used to predict oral bioavailability of drug-like small molecules. Systematic evaluation of more peptides with MW > 500 are needed to determine

1.5. Formulation and Pharmacokinetics

When comparing pharmacokinetic parameters for compounds tested in separate studies, it is important to note possible differences in experimental design. Compounds are usually formulated with a solvent, vehicle, or matrix, which can profoundly affect their solubility, rate and location of dissolution, and permeability across intestinal membranes. Formulation design is a crucial step in drug delivery. Some formulations simply increase chemical stability or solubility at different pH, in aqueous or lipophilic environments. Other formulations are optimized to release the compound at a specific location in the gut, in tissues or in target organs or cells. Often an excipient is added to enhance membrane permeability or oral absorption. Thus, formulation is a key determinant of pharmacokinetic parameters, which are highly dependent on the conditions under which they are measured. Proteins and peptides have been formulated in many ways in attempts to increase oral absorption57−63 including with (i) enzyme inhibitors to reduce proteolysis in the GI tract (e.g., sodium glycocholate, trypsin inhibitors, camostat mesylate, bacitracin, and ovomucoids); (ii) absorption enhancers to improve intestinal permeability (e.g., detergents, surfactants, bile salts, and chelating agents); (iii) mucoadhesive polymers to improve delivery and permeability (PEGs, P(MAA-g-EG), lectin microparticles, and thiolated polymers); (iv) formulation vehicles to protect drug and improve permeability (emulsions, liposomes, cyclodextrins, microspheres, micelles, and nanoparticles). As shown above, absolute oral bioavailability (F%) is defined as the dose-corrected ratio of accumulated concentrations in plasma (AUC) following an iv injection (AUCiv: 100% bioavailability by definition) and an oral dose (AUCpo). This dose-corrected absolute value allows direct comparisons to be made across different studies conducted at different doses. In reality, as dose of the test compound is raised, physio-chemical boundaries and saturation of the biological system will increasingly affect solubility, absorption, active transport mechanisms, and metabolism. Other pharmacokinetic parameters, including AUC and Cmax, are dose-dependent as they are expressed in terms of compound concentration in plasma and will therefore depend on the administered dose. The animal model is an important consideration. Biological variation allows different species, even different strains of the same species, to metabolize drugs in different ways, making comparisons across species and even strains difficult. For technical reasons, it also may not be possible to perform identical experiments in two species, even rodents like mice and 8097


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growth. For 3, LD50 was 226 (iv) and > 850 (p.o.) mg/kg in mice and 66 (iv) and 141 (p.o.) mg/kg in rats.72 Both 2 and 3 contain one D-residue, a D-pipecolic acid in 2 and a D-proline in 3. In solution,73 two intramolecular hydrogen bonds defined a γ- and β-turn in 2, but these were replaced in the crystal structure from chloroform/methanol73 by intermolecular interactions (CCDC code: HEWGOG).

allowable upper limits for molecular properties (MW, logP, HBA, HBD, RotB, and PSA) that influence (a) passive (unassisted) permeability of cells and oral bioavailability and (b) active or facilitated transport mechanisms that promote uptake of peptides > 5 amino acids from the gut. This article takes one important step toward identifying how these molecular properties vary in orally absorbed cyclic peptides.

2. CYCLIC TETRAPEPTIDES Cyclic tetrapeptides are generally RO5 compliant, with MW < 500, HBD = 4, ‘HBA’ = 8, and LogP = 0−5 if bearing hydrophobic side chains. They generally have few rotatable bonds and a small surface area and so, not surprisingly, they are also often orally absorbed and orally bioavailable to some extent. Cyclic tetrapeptides are typically used to stabilize a βturn conformation, with proline and D-amino acids often promoting β-turn formation. 2.1. CJ-15208

Cyclic tetrapeptide CJ-15208 cyclo-(Phe-D-Pro-Phe-Trp) (1, Figure 1), isolated from the fungus C. serratus ATCC 15502, showed dose-dependent antinociceptive activity in mice measured from 20 to 80 min after oral administration (1 mg/ kg p.o.). When given at a higher dose (10 mg/kg p.o.), 1 antagonized a centrally administered selective κ-opioid receptor agonist, suggesting that 1 is brain permeable.70 This cyclic tetrapeptide has only one RO5 violation (MW > 500), a Dproline ring that removes one peptide NH hydrogen bond donor, and hydrophobic side chains, making it suitable for oral absorption.

Figure 2. Apicidin (2) and chlamydocin (3). 2: MW = 624; miLogP = 3.4; HBD = 3; HBA = 11; RotB = 12; tPSA = 139 Å2. 3: MW = 527; miLogP = 0.9; HBD = 3; HBA = 10; RotB = 9; tPSA = 137 Å2.

2.3. Beauveriolides

Beauveriolides (Figure 3) are cyclic tetradepsipeptides, with three amide bonds, one D-residue, and one ester bond, were isolated from the fungus Beauveria sp. FO-6979. Beauveriolides are potential antiatherosclerotic agents that reduce cholesteryl ester synthesis in mouse macrophages via inhibition of acylCoA:cholesterol acyltransferase (ACAT), leading to a reduction in lipid droplet formation in macrophages. Lipid accumulation is associated with the development of atherosclerosis, which can be studied in apoE- or LDL-receptor knockout mice. Beauveriolide III (5) was administered to apoE- or LDLreceptor knockout mice for 2 months (25 mg/kg/day p.o.) and was orally active in mouse models of atherosclerogenesis by inhibiting ACAT activity.74 The ester bond in depsipeptides is not as stable as the amide bond in vivo, but does promote cell permeability before intracellular ester cleavage by esterases.

Figure 1. Cyclic tetrapeptide CJ15208 (1). MW = 578; miLogP = 2.8; HBD = 4; HBA = 9; RotB = 6; tPSA = 120 Å2.

2.2. Apicidin and Chlamydocin

Cyclic tetrapeptides 2 and 3 are analogues of 1 and are RO5 compliant except for MW (Figure 2). Apicidin (2) is a cyclic tetrapeptide metabolite isolated from cultures of F. pallidoroseum. It is a histone deacetylase (HDAC) inhibitor and has been shown to kill protozoa such as Plasmodium sporozoites. When administered in DMSO/PEG400/saline (15:20:65) by oral gavage, oral bioavailability varied slightly (10 mg/kg p.o.; F = 14% (fasting), 19% (nonfasting); Cmax = 235 ng/mL, Tmax = 66 min, t 1/2 = 54 min, V D = 2.5 L/kg, CL = 62 mL.min−1.kg−1)).71 The apicidin-like natural product, chlamydocin (3, Figure 2), was found to inhibit P-815 cell growth in mastocytoma mouse cells and glial tumor rat cells in vitro (ED50 = 0.36 ng/mL). When 3 was administered to tumorinoculated mice (iv and p.o.) there was no antiproliferative activity. The difference between cell and animal findings was attributed to in vivo inactivation of the epoxide in blood. Consistent with this notion, intraperitoneal injections were more effective than intravenous injections in inhibiting tumor

Figure 3. Beauveriolide I (4) and III (5). 4: MW = 488; miLogP = 4.1; HBD = 8; HBA = 8; RotB = 12; tPSA = 114 Å2. 5: MW = 488; miLogP = 4.3; HBD = 3; HBA = 8; RotB = 8; tPSA = 114 Å2.

2.4. HIV Fusion Inhibitors

A critical step in HIV-1 entry into host cells is the protein− protein interaction between CD4 and gp120. Inhibition of this protein−protein interaction (PPI) has been the target of many research groups.75 A library of cyclic peptides was generated to join two noncontinuous regions of CD4-containing key residues Phe43 and Arg59 that interact with gp120.75 A six residue mimic cyclized with succinic acid and ethylenediamine gave cyclic heptapeptide-like 6 (Figure 4). Optimization of the 8098


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linker-length by inserting extra methylene units and replacing residues Gln-Gly-Ser with a pimelic acid moiety enabled inhibition of HIV-1 infection by analogue 7 (Figure 4), which resembles a cyclic tetrapeptide. Despite retention of an arginine, with its protonated guanidine at physiological pH usually being an impediment to absorption, 7 still had reasonable pharmacokinetic properties in rats (1 mg/kg iv: Cmax = 102 ± 19 ng/mL, VD = 0.6 L/kg; 10 mg/kg p.o. in water: Cmax = 866 ± 76 ng/mL, Tmax = 18 min, AUC = 21,770 ± 63 min·ng/mL, t1/2 = 73 min, CL = 14.5 ± 0.3 mL/min·kg, F = 10%).75 Converting 6 to 7 increased RO5 compliance for MW, HBD, HBA, and RotB, halved the tPSA, and significantly increased hydrophobicity. Although these changes make 7 smaller and less polar than 6, and are expected to enhance oral bioavailability, no data for 6 has been reported to confirm this point.

Figure 5. DMP-728 (8). MW = 561; miLogP = −2.3; HBD = 9; HBA = 15; RotB = 8; tPSA = 236 Å2.

3.2. Cyclochlorotine and Astin C

Cyclochlorotine (9, Figure 6) is a hepatotoxic cyclic pentapeptide that was isolated from the common rice-infecting mold P. islandicum.77,78 Its structure consists of natural as well as unnatural L-amino acids, including β-phenylglycine and 3,4dichloro-L-proline. LD50 values were determined in mice (LD50; iv 0.3, sc 0.5, and p.o. 6.6 mg/kg), suggesting some oral absorption.78

Figure 4. HIV fusion inhibitors (6) and cyclic tetrapeptide-like (7). 6: MW = 775; miLogP = −5.2; HBD = 15; HBA = 22; RotB = 13; tPSA = 363 Å2. 7: MW = 488; miLogP = −0.3; HBD = 8; HBA = 11; RotB = 9; tPSA = 184 Å2.

Figure 6. Structures of cyclochlorotine (9) and astin C (10). 9: MW = 572; miLogP = −2.5; HBD = 6; HBA = 12; RotB = 4; tPSA = 177 Å2. 10: MW = 570; miLogP = −1.0; HBD = 5; HBA = 11; RotB = 4; tPSA = 157 Å2.

3. CYCLIC PENTAPEPTIDES Cyclic pentapeptides generally have HBD = 5, HBA = 10, LogP = 0−5 if bearing hydrophobic side chains, but their molecular weights usually exceed 500, resulting in more rotatable bonds and larger surface areas. To be orally absorbed, they often require synthetic modifications.

Astin C (or Asterin, 10, Figure 6), a close analogue of 9 is a plant cyclic peptide isolated from the roots of A. tataricus. The crystal structure of 10 from chloroform/methanol (CCDC code: WILXEW) showed a single transannular hydrogen bond from an Abu NH to the (i, i+3) carbonyl of the β-phenylglycine carbonyl.79 The remaining hydrogen bond donors and acceptors are highly solvent exposed. Inflammatory bowel disease is characterized by activation of T lymphocytes. Astin C has been shown to lower mouse serum concentrations of TNF, IL-4, IL-17, and to induce apoptosis in activated T cells. Daily oral dosing of astin C (2 or 4 mg/kg/day p.o. in 5% methylcellulose in saline) was shown to protect mice against TNBS-induced colonic inflammation.80

3.1. DMP-728

DMP-728 (8, Figure 5) is a potent and specific antagonist of platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa). Like 6 and 7, compound 8 contains an arginine residue that is normally detrimental to oral absorption. It consists of four conventional amino acids, including a D-Abu, residues with N- and C-termini linked by a fifth, unnatural, hydrophobic amino acid, 3aminomethybenzoic acid. The pharmacokinetic profile for 8 was measured following oral administration with or without absorption enhancers to rats (10 mg/kg iv, 8 mg/kg p.o. with palmitoylcarnitine chloride; Cmax = 0.44 ± 0.21 μg/mL, Tmax = 0.75 h, AUC = 1.38 ± 0.56 μg·h/mL, t1/2 = 2.8 ± 2.1 h, F = 14.6%) and dogs (2 mg/kg iv, 2 mg/kg p.o. with palmitoylcarnitine chloride; Cmax = 0.41 ± 0.10 μg/mL, Tmax = 1.0 h, AUC = 1.09 ± 0.22 μg·h/mL, t1/2 = 3.3 ± 0.9 h, F = 20.5%).76 Absorption enhancers significantly improved pharmacokinetic parameters compared to controls formulated in microcapsules. The MW, LogP, HBD, and tPSA all violate limits usually associated with passively diffusing, orally bioavailable, drug-like small molecules. We speculate that the N-methyl arginine might promote active transport of this compound across the intestinal membrane.

3.3. BL3020-1

α-Melanocyte stimulating hormone (α-MSH) is a 13-residue peptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-LysPro-Val) that stimulates the release of melanin by skin melanocytes. α-MSH also binds to the melanocortin 4 receptor (MC4R), which modulates food intake and energy utilization.81 The tetrapeptide sequence His-Phe-Arg-Trp, and other analogues derived from α-MSH, decrease food intake and elevate energy utilization upon binding to MC4R, making them attractive targets as antiobesity drugs.82 However, they suffer from metabolic instability and poor intestinal permeability. A backbone-cyclized α-MSH analogue based on Phe-D-Phe-ArgTrp-Gly-NH2, activated MC4R and had increased oral bioavailability. One analogue, BL3020-1 (11, Figure 7) was MC4R selective, had good permeability in the Caco-2 model, 8099


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HDACs. Largazole has been synthesized by multiple routes allowing many derivatives to be produced.86−91 A crystal structure of 13 bound to HDAC 8 (PDB code: 3RQD) shows a single NH directed to the center of the macrocycle but no strong evidence of intramolecular hydrogen bonding.92 Largazole analogues cocrystallized with HDAC 8 also do not show any intramolecular hydrogen bonds (PDB codes: 4RN1, 4RN2).93 Pharmacokinetic parameters measured in rats showed that 13 was unstable in vivo and rapidly cleared after a single iv dose (10 mg/kg iv in EtOH/DMSO/PEG400/saline (1:1:1:2); CL = 76 ± 18 L/h·kg, t1/2 = 0.5 ± 0.1 h, AUC = 134 ± 29 μg· h/mL, VD = 27 ± 11 L/kg, Cmax = 280 ± 64).94 Largazole 13, Boc-L-cysteine-largazole disulfide 14, and disulfide homodimer 15 (Figure 9) were administered orally (50 mg/kg p.o. in polyethylene glycol/glycerol/EtOH/DMSO 60:15:15:15:10) to female nude mice.95 Oral activities were measured through in vivo hyperacetylation of harvested HCT116 tumors. Only 13 produced hyperacetylated histones, however largazole free thiol was found in tumors from animals orally dosed with 13, 14, or 15, indicating that all three derivatives displayed some oral absorption in mice.

and enhanced metabolic stability in rat brush border membrane vesicles (BBMVs). A single oral dose administered to rats (0.5 mg/kg p.o. dissolved in water) led to reduced food consumption, while repetitive daily oral dosing reduced weight gain in rats.82 Pharmacokinetic parameters measured in rats following iv administration (1 mg/kg iv in H2O) indicated t1/2 > 105 min and VD = 2.1 L/kg. Oral administration (10 mg/kg p.o. in H2O) to rats showed AUC = 24980 ng·min/mL, Cmax = 202 ± 39 ng/mL, Tmax = 37 ± 10 min, and F = 8.5%. We speculate that charged residues in this compound may help promote intestinal absorption via facilitated transport. Interestingly, concentrations of ∼5 ng/mL were also found in brain tissue, indicating some ability of 11 to cross the blood brain barrier.82

Figure 7. Structure of BL3020−1 (11). MW = 836; miLogP = −0.8; HBD = 12; HBA = 18; RotB = 13; tPSA = 287 Å2.

3.4. Romidepsin Figure 9. Structures of largazole (13), its Boc-L-cysteine disulfide derivative (14), and its disulfide dimer (15). 13: MW = 623; miLogP = 5.3; HBD = 2; HBA = 9; RotB = 12; tPSA = 127 Å2. 14: MW = 716; miLogP = 2.8; HBD = 4; HBA = 13; RotB = 12; tPSA = 185 Å2. 15: MW = 991; miLogP = 3.6; HBD = 4; HBA = 16; RotB = 11; tPSA = 220 Å2.

Romidepsin (Istodax, FK-228, 12, Figure 8) is a cyclic peptide HDAC inhibitor that possesses potent antitumor activity against a variety of human cancer cell lines and xenografts.83,84 It contains D-cysteine, D-valine, and (3S,4E)-3-hydroxy-7mercapto-4-heptenoic acid residues. Romidepsin is an RO5compliant and orally active prodrug, reduction leading to a bisthiol, one of which covalently bonds to the catalytic zinc ion in HDAC enzymes. It was administered orally to mice with human prostate tumor xenographs (3 × 50 mg/kg/wk p.o.),84 and was also significantly absorbed after oral administration to rats (10 mg/kg iv; Cmax = 1829 ± 359 ng/mL, VD = 22 ± 7 L/ kg, t1/2 = 5.9 ± 1.2 min, AUC = 25409 ± 8767 ng/mL·min.; 50 mg/kg p.o., AUC = 19712 ± 9168 ng/mL·min, F = 16 ± 7%).83

3.6. Complement C5aR Antagonists

3D53 (16, Figure 10), later known as PMX53,96 is a derivative of the C-terminal turn of human complement protein C5a and is a potent antagonist of the human C5a receptor C5aR1 (IC50 3 nM against 3 nM C5a).96−100 The Fairlie group designed 3D53 and a range of cyclic pentapeptides97−99 featuring an endocyclic D-cyclohexylalanine and L-arginine that are important for binding, an aromatic residue (L-tryptophan or Lphenylalanine) that is required for antagonism, an L-proline turn-inducing constraint, and an exocyclic aromatic ring (Lphenylalanine in 16 or a phenyl propionyl group in 3D624 (later called PMX205)) for affinity.99 NMR structural studies of 16 and analogues in DMSO-d6 indicated a turn motif.99 Compound 16 is a classic example where oral activity is observed despite low oral bioavailability, due to a long residence time on the receptor (t1/2 ≈ 20 h) overcoming low systemic availability (F = 1−2%, rat).100 This compound and its analogues display efficacy in vivo in over 20 rat and mouse models of human disease following oral administration.96

3.5. Largazole

Largazole (13, Figure 9) is a cyclic depsipeptide natural product isolated from Symploca sp. collected from the Florida Keys.85 Largazole is one of the most potent HDAC inhibitors known, with activity at low nM concentrations and selectivity for class I

3.7. Actinomycin D

Actinomycin D (17, Figure 11) is an antibiotic natural product from a family of actinomycins first isolated in 1940.101 It features two cyclic pentapeptides, each with an L-proline and two N-methyl amino acids, bridged by a phenoxazinone linker.

Figure 8. Structure of romidepsin (12). MW = 541; miLogP = 1.6; HBD = 4; HBA = 10; RotB = 2; tPSA = 143 Å2. 8100


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p.o. in olive oil: AUC = 442 ng·h/mL, Cmax = 187 ng/mL, F = 4%), 19 (1 mg/kg iv in DMSO: CL = 4.7 mL/min·kg, VD = 0.19 L/kg, t1/2 = 1.0 h; 10 mg/kg p.o. in olive oil; AUC = 6289 ng·h/mL, Cmax = 1900 ng/mL, F = 18%), and 20 (1 mg/kg iv in DMSO: CL = 24.1 mL/min·kg, VD = 0.75 L/kg, t1/2 = 1.2 h; 10 mg/kg p.o. in olive oil; AUC = 642 ng·h/mL, Cmax = 174 ng/ mL, F = 9%). Despite being larger with more RO5 violations (Figure 12), 19 had better oral bioavailability than 18, and was comparable to cyclosporin A (F = 21%) under the same conditions.106 Figure 10. Structure of 3D53 (16). MW = 896; miLogP = 1.0; HBD = 11; HBA = 18; RotB = 14; tPSA = 273 Å2.

A crystal structure of actinomycin C in complex with deoxyguanosine showed two intramolecular hydrogen bonds between the two Val residues keeping the macrocycles close together to help insert the phenoxazinone into DNA (CCDC code: ACTDGU10).102 This preorganization minimized solvent exposure to polar atoms. Similar structures in the absence of nucleotides (CCDC codes: BEJXET, BRAXGU, GIDNUC, POHMUU) show stacking of the cycles but the Val···Val hydrogen bonds remain. These cycle−cycle interactions loosened in crystal structures of 17 bound to short sequences of DNA (PDB codes: 4HIV, 1I3W).103,104 Actinomycin D suppresses transcription, is cytotoxic and effective in treating various tumors. It has an estimated bioavailability F = 5% based on adverse systemic effects after oral versus iv administration over 2 weeks.105 LD50 values for 17 were determined in mice (LD50 7.8 mg/kg p.o.) and rats (LD50 iv 0.4, p.o. 7.2 mg/kg).

Figure 12. Cyclic pentaleucine (18) and cyclic hexaleucines (19, 20). 18: MW = 566; miLogP = 3.9; HBD = 5; HBA = 10; RotB = 10; tPSA = 145 Å2. 19: MW = 679; miLogP = 4.7; HBD = 6; HBA = 12; RotB = 12; tPSA = 174 Å2. 20: MW = 679; miLogP = 4.7; HBD = 6; HBA = 12; RotB = 12; tPSA = 175 Å2.

4. CYCLIC HEXAPEPTIDES Cyclic hexapeptides and larger macrocycles generally contravene RO5 parameters, with MW > 500, HBD ≥ 6, HBA ≥ 12, LogP = 0−5 if bearing hydrophobic side chains. They have more rotatable bonds and larger surface areas than the smaller cyclic peptides above. 4.1. Desmopressin

Desmopressin (21, Figure 13) was first reported in 1966 as an analogue of vasopressin (antidiurectic hormone). Its deaminated cysteine at position 1 and D-arginine at position 8 enhanced metabolic stability and antidiuretic effects. The bioavailability of desmopressin in normal healthy adults was low following intranasal administration (F = 3−5%) and very low after oral delivery (F = 0.08−0.16%).107−110 4.2. Melanotan II

Figure 11. Structure of actinomycin D, (17). MW = 1255; miLogP = 0.8; HBD = 6; HBA = 28; RotB = 8; tPSA = 360 Å2.

Melanotan II (22, Figure 14) is a cyclic hexapeptide analogue of α-melanocyte-stimulating hormone that was developed as a tanning agent to help prevent skin cancer. It displayed some

3.8. Leucine Cyclic Peptides

A selection of three all-leucine cyclic peptides (Figure 12), cyclo-[(L-Leu)5] (18), cyclo-[(L-Leu)6] (19), and cyclo-[(LLeu)5(D-Leu)] (20), were synthesized and orally administered to rats.106 These compounds are at the boundary limits of RO5 guidelines for molecular weight, hydrogen bond donors/ acceptors. Their other properties (LogP, rotatable bonds, tPSA) depend upon substituents on the cyclic peptide scaffold. NMR, CD and X-ray structural studies on 18−20 did not show intramolecular hydrogen bonds, but intermolecular interactions for 18 were consistent with evidence for aggregation in solution.106 Despite lacking N-methyl groups or depsipeptide bonds to reduce the number of hydrogen bond donors, all three compounds showed oral absorption: 18 (1 mg/kg iv in DMSO: CL = 13.1 mL/min·kg, VD = 0.36 L/kg, t1/2 = 0.5 h.; 10 mg/kg

Figure 13. Structure of desmopressin (21). MW = 1069; miLogP = −4.3; HBD = 18; HBA = 26; RotB = 20; tPSA = 435 Å2. 8101


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administration (250 mg/kg p.o.: AUC0−48h = 23.3, 26.5, 17.7, and 6.9 μg·h/mL, respectively; Cmax = 1.6, 1.5, 0.6, and 0.3 μg/ mL, respectively). The effect of different meal treatments (fasted, mixed meal, lipid meal, protein meal, or carbohydrate meal) prior to identical oral dosing was also investigated (250 mg/kg p.o.; AUC0−48h = 21.2 ± 5.8, 8.9 ± 2.6, 7.5 ± 1.8, 8.9 ± 2.8, and 25.2 ± 5.1 μg·h/mL, respectively. Cmax = 1.1 ± 0.3, 0.5 ± 0.17, 0.4 ± 0.13, 0.5 ± 0.2, and 1.6 ± 0.3 μg/mL, respectively).117 Low oral absorption of 24 in humans was reported in early clincal trials (F = 2−7%).119 A similar compound, caspofungin (25), displayed poor oral absorption in rats (50 mg/kg p.o., F < 0.2%).120 Micafungin (26) is an antifungal agent approved for intravenous use by the USFDA in 2005 and in several other countries. It is a further modified echinocandin analogue primarily used against Candida infections in HIV-positive patients. It is an inhibitor of beta1,3-D-glucan synthase, essential for fungal cell wall synthesis. It is poorly orally absorbed.121,122

bioavailability after oral administration to rats (0.3 mg/kg iv, 6.76 mg/kg p.o., F = 4.6%) despite violating all RO5 and related parameters (Figure 14).111

Figure 14. Structure of melanotan II (22). MW = 1024; miLogP = −0.1; HBD = 16; HBA = 24; RotB = 18; tPSA = 382 Å2.

4.3. Oxytocin

Oxytocin (23, Figure 15) is a disulfide-bridged cyclic hexapeptide hormone with an additional three amino acids outside the cycle. This mammalian neurotransmitter and hormone is associated with numerous physiological responses. It is currently used in the clinic to induce childbirth and lactation.112,113 All physicochemical parameters listed in Figure 15 violate guidelines for oral bioavailability. An NMR structure for oxytocin in water showed two transannular mainchain hydrogen bonds (Asn NH···OC Tyr, Cys NH···OC Tyr),114 which likely reduce the 3D PSA from the nominal tPSA value. A crystal structure of a des-amino derivative of oxytocin (PDB codes: 1XY1, 1XY2; CCDC code: DUPFAV) showed a hydrogen bond defining a β-turn for the YIQN motif, and a Tyr NH···OC Asn transannular hydrogen bond along with the disulfide bond bracing the structure.115 Nevertheless, the oral bioavailability of oxytocin is very low in rats (F = 0.9%), requiring it to be injected for efficacy.116

Figure 16. Structures of anidulafungin (24), caspofungin (25), and micafungin (26). 24: MW = 1140; miLogP = −0.8; HBD = 14; HBA = 24; RotB = 14; tPSA = 377 Å2. 25: MW = 1093; miLogP = −4.6; HBD = 18; HBA = 25; RotB = 23; tPSA = 412 Å2. 26: MW = 1270; miLogP = −5.3; HBD = 17; HBA = 32; RotB = 18; tPSA = 510 Å2.

Figure 15. Structure of oxytocin (23). MW = 1007; miLogP = −3.7; HBD = 16; HBA = 24; RotB = 17; tPSA = 400 Å2.

4.5. Somatostatin, Octreotide, and Analogues

Somatostatin-14 (27) is a growth hormone-inhibiting peptide resulting from cleavage of its 166 residue preproprotein that is differentially expressed in tissues and regulates endocrine function. Potential therapeutic applications of somatostatin-14 were quickly recognized, however its low half-life in plasma (∼2 min) made it an unsuitable drug candidate. Many analogues (e.g., Figure 17) were developed to improve pharmacokinetic properties. Bicyclic 28 displayed potent biological activity. Contracting this cycle by removing nonessential amino acids gave 29. These analogues, in particular 28, retained potency in vitro and in rats. Their metabolic stability improved relative to somatostatin-14, however, no oral bioavailability was reported.123

4.4. Anidulafungin, Caspofungin, and Micafungin

Anidulafungin (LY303366, Eraxis, 24, Figure 16) is a lipidmodified cyclic peptide analogue of echinocandin B.117 Pharmacokinetic parameters were measured in female Beagle dogs following oral and intravenous administration (5 mg/kg iv: t1/2 = 15.6 h; CL = 0.10 ± 0.02 L/h·kg, VD = 1.76 ± 0.11 L/ kg, AUC0‑∞ = 49409 ± 10286 ng·h/mL; 5 mg/kg p.o.: Cmax = 307 ± 61 ng/mL, Tmax = 4.7 ± 1.2 h, AUC0‑∞ = 4477 ± 768 ng· h/mL, F = 9%).118 Region-dependent intestinal absorption and meal composition effects on Cmax and AUC were found for dogs given the same dose via oral, duodenal, jejunal or colonic 8102


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Figure 18. Cyclic somatostatin analogues. Cyclic hexapeptide (30) and tri-N-methylated analogue (31). 30: MW = 807; miLogP = 0.5; HBD = 9; HBA = 15; RotB = 11; tPSA = 228 Å2. 31: MW = 849; miLogP = 1.3; HBD = 6; HBA = 15; RotB = 11; tPSA = 201 Å2.

turn in the macrocyclic ring and 2 hydrogen bonds between side chains. The α-helical conformations contained 2 internal and 2 side chain-side chain hydrogen bonds. In the solid state, crystals of octreotide from aqueous oxalic acid (CCDC code: YICMUS) contained two hydrogen bonds in linked β-turns about the FwKT and wKTC motifs which, in conjunction with the disulfide, produce a very rigid molecule.129 Octreotide resisted degradation by enzymes and tissue homogenates. When injected into rats and monkeys, octreotide showed the greatest inhibition of growth hormone, insulin and glucagon production. Furthermore, octreotide was better tolerated than somatostatin and had ≥20 times longer duration of action.126 Octreotide is orally active126,130,131 but the dose-corrected systemic oral bioavailability relative to subcutaneous administration is very low (F = 0.3%).130

Figure 17. Structures of somatostatin and cyclic analogues (28−29). Somatostatin (27): MW = 1638; miLogP = −5.4; HBD = 26; HBA = 37; RotB = 26; tPSA = 613 Å2. 28: MW = 1404; miLogP = −0.7; HBD = 19; HBA = 27; RotB = 19; tPSA = 428 Å2. 29: MW = 894; miLogP = 0.1; HBD = 11; HBA = 17; RotB = 9; tPSA = 266 Å2.

Replacing the -Cys-Aha-Cys- motif in 29 with the simpler -Phe-Pro- motif gave analogue 30. Compounds 27 and 30 both significantly reduced the effects of growth hormone following sc injection to rats. Somatostatin-14, 27, and 30 were administered orally to rats (25 mg/kg p.o.). Somatostatin failed to lower growth hormone levels, 28 reduced levels at 1 h but not at 2 h, while 30 reduced levels for at least 3 h. Peptide 28 was cleaved slowly by trypsin at a similar rate to 29.124 To improve oral bioavailability and other pharmacokinetic properties, 30 N-methylated analogues of 30 were synthesized.125 Compound 30 and tri-N-methylated analogue 31 (Figure 18) were administered orally to rats (10 mg/kg p.o.). Oral bioavailability of 30 could not be determined, whereas 31 showed some oral absorption (F = 10%). Other pharmacodynamic properties showed that 31 had an extended elimination half-life (74 vs 15 min) and increased steady state VD (3.7 vs 0.3 L/kg) relative to 30.125 Bauer (Sandoz Ltd.) reported a series of somatostatin-14 analogues based on a disulfide cyclized hexapeptide 32 containing an L-Phe-D-Trp-L-Lys motif (Figure 19).126 Cyclic hexapeptide 32 was much less active than somatostatin-14 when tested in rats and monkeys. To regain activity, D-Phe was added to the N-terminus to mimic the natural Phe-6 and significantly improved in vivo potency. Addition of threonol to the C-terminus to mimic the natural Thr-12 gave octreotide (33, Sandostatin, Figure 19). NMR solution structural studies of octreotide127 and close analogues128 in DMSO-d6 (PDB codes: 1SOC, 2SOC, 1YL8, and 1YL9) showed a mixture of βsheet and partially α-helical motifs. The β-sheet like structures contained 5 internal hydrogen bonds, 2 transannular and 1 β-

Figure 19. Somatostatin analogue 32 and octreotide (33). 32: MW = 784; miLogP = −1.8; HBD = 13; HBA = 16; RotB = 10; tPSA = 277 Å2. 33: MW = 1019; miLogP = −2.0; HBD = 15; HBA = 20; RotB = 17; tPSA = 332 Å2.

SDZ CO 611 (Ilatreotide, 34, Figure 20) is a D(+)-maltose N-terminally modified amadori derivative of octreotide 33. SDZ CO 611 (34) displayed improved metabolic stability supposedly leading to enhanced oral absorption in rats (F = 1.1%).132 Intravenous infusion of somatostatin and sc injection of octreotide 33 suppress pancreatic and gastrointestinal hormones and accelerate early gastric emptying. Octreotide 33 also prolongs mouth to cecum transit time (MCTT). When administered orally (1 or 5 mg p.o. twice daily) to healthy males, 34 was equally effective as sc 33 in suppressing preprandial hormone levels, early gastric emptying and prolonging MCTT.133 8103


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Figure 20. SDZ CO 611 (ilatreotide, 34). MW = 1344; miLogP = −4.9; HBD = 21; HBA = 32; RotB = 23; tPSA = 488 Å2.

4.6. Beauvericin and Enniatins Figure 21. Beauvericin (35), enniatins A (R = Ile, 36), B (R = Val, 37), and C (R = Leu, 38), and enniatin B1 (39). 35: MW = 784; miLogP = 6.5; HBD = 0; HBA = 12; RotB = 9; tPSA = 140 Å2. 36: MW = 682; miLogP = 6.0; HBD = 0; HBA = 12; RotB = 9; tPSA = 140 Å2. 37: MW = 640; miLogP = 4.5; HBD = 0; HBA = 12; RotB = 6; tPSA = 140 Å2. 38: MW = 682; miLogP = 6.1; HBD = 0; HBA = 12; RotB = 9; tPSA = 140 Å2. 39: MW = 654; miLogP = 5.0; HBD = 0; HBA = 12; RotB = 7; tPSA = 140 Å2.

Beauvericin (35, Figure 21) is a symmetrical cyclic hexadepsipeptide consisting of three repeating units of the dipeptides N-methyl-L-phenylalanine and the D-valine surrogate (R)-hydroxyisovaleric acid. There are no HBD in 35 or its analogues 36−39, few rotatable bonds and low tPSA, but they do have RO5 violations for MW, HBA, and LogP (Figure 21). The crystal structure of beauvericin hydrate134 from n-heptane (CCDC code: BEVERC) did not show intramolecular hydrogen bonds; however, solvent exposure of the hydrogen bond acceptors was evidenced in the solid state by complexation of barium salts (CCDC code: BEAVBA).135 Compound 35 was first isolated from B. bassiana136 and inhibited cytochrome P450 enzymes. Pharmacokinetic data following oral administration at various doses to rats (0.5, 1.0, 2.0 mg/kg p.o.: Cmax = 3.4, 5.4, 13.9 mg/L; Tmax = 4.1, 4.3, 5.4 h; CL = 0.29, 0.21, 0.32 mL/min·kg; AUC0‑∞ = 29, 80, 103 h·mg/L; t1/2 = 2.9, 3.6, 3.0 h, respectively)137 but no iv data was reported making it difficult to estimate oral absorption. LD50 of 35 has been reported in mice (LD50 ip >10 mg/kg, p.o. >100 mg/ kg).138,139 The beauvericin scaffold is shared by enniatins AC140 (Figure 21, 36−38), where L-phenylalanine is substituted by L-isoleucine (36), L-valine (37), or L-leucine (38), respectively. Several crystal structures of 37 and 38 have been reported (CCDC entries DESYIJ, BICMEF, CIKJAH, ZASQOZ, QEMCAM). As for beauvericin, there were no intramolecular hydrogen bonds.141,142 However, 37 did complex rubidium143 and potassium144 ions, indicating a solvent accessible polar surface (CCDC codes: MVHIRB10, PEKFEQ). Pharmacokinetic data were estimated for 37 from in vitro assays.145 The toxicokinetic profile of enniatin B1 (39, Figure 21) was measured in piglets (0.05 mg/kg iv or p.o. in 2% EtOH/water). Compound 39 was highly orally bioavailable (F 91%) but was cleared rapidly (t1/2 = 0.15 h, CL = 2.00 L/h·kg) with low oral plasma exposure (AUC = 25.3 ng·h/mL).146

confirmed oral activity in infants by determining the concentration of 40 in urine 24 h post oral dosage.148

Figure 22. Nepadutant (40). MW = 947; miLogP = −1.6; HBD = 11; HBA = 22; RotB = 11; tPSA = 348 Å2.

4.8. Bouvardin

Bouvardin (41, Figure 23) is a cyclic hexapeptide containing three N-methyl amides, one O-methylated tyrosine, one D-Ala, and an additional diphenylether-bridge between two tyrosine side chains. The crystal structure of 41 from methanol/water (CCDC code: BOUVAR) did not show internal hydrogen bonds but was in an extended conformation induced by the oxidatively fused tyrosine side chains. This bridged constraint also introduced a cis-amide bond between the two residues.149 It was isolated from B. ternifolia and showed in vitro cytotoxicity against P388 lymphocytic leukemia and B16 melanotic melanoma cell lines. Bouvardin and an acetylated deoxybouvardin derivative 42 (Figure 23) had LD50 values of 10 mg/kg (42, ip), 229 mg/kg (41, p.o.), and 20 mg/kg (42, iv) in mice, indicating that 41 is orally absorbed.150 These

4.7. Nepadutant

Nepadutant (40, Figure 22) is a glycosylated, bicyclic hexapeptide tachykinin NK2 receptor antagonist. Cyclisation is achieved through both head-to-tail and side chain-to-side chain linkages and an aminohexose is attached to an asparagine side chain. The aminohexose moiety gives the structure amphiphilic character. Compound 40 was given orally to mice (38 mg/kg p.o. in castor oil; Tmax = 2.7 ± 0.7 h, Cmax = 1401 ± 220 nM, t1/2 = 11.7 ± 0.9 h, AUC = 8463 ± 2635 nmol·h/mL, F = 5%).147 Pediatric phase 1 clinical studies 8104


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t1/2 = 55 min, AUC0−24h = 4.5 mg·h/kg; 160 mg/kg p.o.: Cmax = 10.4 mg/L, t1/2 = 76.2 min, AUC0−24h = 11.34 mg·h/kg).152

compounds have few hydrogen bond donors and few rotatable bonds, but they have high polar surface areas and low LogP.

Figure 23. Bouvardin (41) and acetylated derivative 42. 41: MW = 773; miLogP = 0.5; HBD = 5; HBA = 16; RotB = 3; tPSA = 207 Å2. 42: MW = 799; miLogP = 1.2; HBD = 3; HBA = 16; RotB = 5; tPSA = 193 Å2.

Figure 25. Antibacterial drug, NXL103 consisting of linopristin (45) and floprestin (46). 45: MW = 950; miLogP = 1.6; HBD = 4; HBA = 19; RotB = 9; tPSA = 223 Å2. 46: MW = 532; miLogP = 1.5; HBD = 2; HBA = 9; RotB = 1; tPSA = 122 Å2.

4.9. Pristinamycin and Related Antibiotics

Pristinamycin is an oral antibiotic consisting of two synergistic, but structurally unrelated, components. Separately, the compounds exhibit bacteriostatic activity, while the combination of pristinamycin IA (43) and IIA (44, Figure 24) has bactericidal activity. 43 has one L-Pro, one N-methylated amide, a D-Abu, and a 4-oxopiperidine incorporated into its backbone. 44 bears a hybrid terpenoid/peptide backbone rigidified by three alkenyl bonds, a 4,5-dehydroproline, and an oxazole ring. A study in an Australian hospital investigated the effectiveness of oral pristinamycin in patients with various bacterial infections.151 Patients were dosed orally with 500−1000 mg of 43 and 44 on multiple days. Of 46 patients, five were excluded due to side effects, 10 were cured from infection, and 21 had infections suppressed.

4.10. 1-NMe3 and Related Cyclic Hexapeptides

To permeate through membranes, molecules must transition from aqueous to hydrophobic and back to aqueous phases. Conformational changes might facilitate this process by lowering desolvation energies. To test this idea, molecular modeling, H-D exchange experiments, and permeability measurements were combined to produce passively permeable cyclic hexapeptide diastereomers from cyclo-[Leu-Leu-LeuLeu-Pro-Tyr]153 (Figure 26). None of the diasteromers had Nmethyl groups; however, one compound, cyclo[Leu-D-Leu-LeuLeu-D-Pro-Tyr], showed a conformational change between CDCl3 and water by molecular modeling. This diastereomer was the least permeable in the initial series even though higher permeability had previously been reported for the same peptide.154 In further studies, tri-N-methylation yielded 1NMe3 47 which had good PAMPA permeability and oral bioavailability in rats (1 mg/kg iv: CL = 4.5 mL/min·kg, VD = 1.1 L/kg; 10 mg/kg p.o.: AUC = 10.5 ng·h/mL, Cmax = 852 ng/ mL, F = 28%).155 Analogues of 47 varied a single side chain substitution to learn effects on pharmacokinetic profiles.156 An N-methyl-leucine was substituted for N-methyl-serine (48), Nmethyl-threonine (49), N-methyl-aspartate (50), or N-methyllysine (51). Their pharmacokinetic profiles revealed that increasing side chain polarity reduced oral absorption. Interestingly, threonine analogue 49 (1 mg/kg iv: CL = 63.6 mL/min·kg, VD = 3.8 L/kg, t1/2 = 1.0 h; 10 mg/kg p.o.: AUC = 201 ng·h/mL, Cmax = 105 ng/mL, F = 24%) displayed similar pharmacokinetics as 47, while serine analogue 48 had low oral absorption (1 mg/kg iv: CL = 60.4 mL/min·kg, VD = 4.3 L/kg, t1/2 = 1.5 h; 10 mg/kg p.o.: AUC = 42.3 ng·h/mL, Cmax = 9.86 ng/mL, F = 2%). Aspartate analogue 50 (1 mg/kg iv: CL = 56.4 mL/min·kg, VD = 0.36 L/kg, t1/2 = 0.4 h; 10 mg/kg p.o.: AUC = 18.7 ng·h/mL, Cmax = 17.3 ng/mL, F < 1%) and lysine analogue 51 (1 mg/kg iv: CL = 10.4 mL/min·kg, VD = 0.9 L/ kg, t1/2 = 1.0 h; 10 mg/kg p.o.: AUC = 18.1 ng·h/mL, Cmax = 18.3 ng/mL, F < 1%) had negligible oral bioavailability (F < 1%). NMR structural studies of this series of peptides153−155 in CDCl3 and DMSO-d6 suggested that the pattern of internal hydrogen bonds was strongly conserved. The same orally bioavailable scaffold (47) inspired further investigations to better understand and improve passive permeability of cyclic hexapeptides. N-Methylamino acid-to-

Figure 24. Antibacterial combination drug, pristinamycin consisting of pristinamycins IA (43) and IIA (44). 43: MW = 867; miLogP = 0.7; HBD = 4; HBA = 18; RotB = 7; tPSA = 228 Å2. 44: MW = 526; miLogP = 0.7; HBD = 2; HBA = 10; RotB = 1; tPSA = 139 Å2.

NXL103 (XRP2868; Figure 25) is also an antibiotic cocktail made of linopristin 45 and floprestin 46 (30:70 mixture). These compounds replace three hydrogen bond donor NHs with 5 or 6 membered rings and a depsipeptide ester, 45 also has an Nmethyl group. Pharmacokinetic parameters were measured after oral administration at multiple doses to cyclophosphamideinduced neutropenic mice infected with strains of S. pneumoniae (NXL103: 10 mg/kg p.o.: Cmax = 0.32 mg/L; 40 mg/kg p.o.: Cmax = 0.8 mg/L, t1/2 = 21 min; 80 mg/kg p.o.: Cmax = 4 mg/L, 8105


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enter cells and interact with intracellular targets. β-hydroxy-γamino acids were used to create cyclic hexapeptides based on 47. Oral bioavailability in rats was reported for one compound, 55, displaying promising passive permeability (1 mg/kg iv: CL = 10 mL/min·kg, VD = 1.1 L/kg, t1/2 = 1.6 h; 5 mg/kg p.o.; AUC = 1697 ng·h/mL, Cmax = 324 ng/mL, F = 21%).158 Although good permeability was maintained in the less peptidic 55, its oral bioavailability and plasma concentration (AUC) were worse than for 47. Interestingly, NMR evidence suggested that, despite variability in the membrane permeability of some peptoid and statin-type analogues of 47, these compounds still retained the two internal hydrogen bonds shown in Figure 27.157,158 Other groups have used 47 and analogues to investigate effects of N-methylation,159 correlating amide NH NMR temperature coefficients with cell permeability160 and flexibility/rigidity.161 A crystal structure of 47 (CCDC code: AHELEG) indicated a saddle-like structure incorporating two β-turns at either end, with one close hydrogen bond in each (2.0, 2.5 Å, indicated by dotted lines, Figure 26).159 Novartis researchers compared the original scaffold of 47 with its non-Nmethylated counterpart (56, Figure 28) and showed that Nmethylation was important for oral absorption. Permeability enhancers did not improve oral bioavailability of 47. Pharmacokinetics were measured in mice for non-N-methylated analogue 56 (3 μM/kg iv: CL = 82 mL/min·kg, VD = 0.8 L·kg, t1/2 = 0.2 h, AUCiv = 292 nM·h; 10 μM/kg p.o.: AUCpo = 5.7 nM·h, Cmax = 2.9 nM, Tmax = 0.6 h, F = 2%) and 47 (3 μM/kg iv: CL = 1 mL/min·kg, VD = 0.4 L/kg, t1/2 = 22 h, AUCiv = 29618 nM·h; 10 μM/kg p.o.: AUC = 8967 nM·h, Cmax = 534 nM, Tmax = 3.8 h, F = 30%). These striking results highlight good oral absorption for 47 in rodents.

Figure 26. 1-NMe3 (47) and derivatives (48−51). 47: MW = 755; miLogP = 4.1; HBD = 3; HBA = 13; RotB = 10; tPSA = 160 Å2. 48: MW = 729; miLogP = 1.8; HBD = 4; HBA = 14; RotB = 9; tPSA = 180 Å2. 49: MW = 743; miLogP = 2.1; HBD = 4; HBA = 14; RotB = 9; tPSA = 180 Å2. 50: MW = 757; miLogP = 1.9; HBD = 4; HBA = 15; RotB = 10; tPSA = 197 Å2. 51: MW = 770; miLogP = 2.3; HBD = 5; HBA = 14; RotB = 12; tPSA = 186 Å2. Dotted lines indicate hydrogen bonds observed in crystal structure of 47, and NMR solution structures of analogues.

peptoid substitutions were explored in cyclic hexapeptide/ peptoid hybrids (Figure 27). Peptoid substitutions that replaced one (52) or two (53) of the three N-methyl amides facilitated permeability across a monolayer of low efflux epithelial MDCK cells. Interestingly, replacing all three Nmethyl moieties with peptoid units (54) generated a macrocycle that was less permeable.157 β-Hydroxy-γ-amino acids are naturally occurring peptidomimetic surrogates that structurally resemble a peptide backbone by replacing heteroatoms with carbon to minimize polarity. These substructures may have evolved to allow molecules to

Figure 28. Non-N-methylated analogue 56 and bis-N-methylated analogue 57 with a different N-methylation pattern to 47 retained oral bioavailability. 56: MW = 713; miLogP = 3.3; HBD = 6; HBA = 13; RotB = 10; tPSA = 186 Å2. 57: MW = 741; miLogP = 3.8; HBD = 4; HBA = 13; RotB = 10; tPSA = 168 Å2. Dotted lines indicate conserved hydrogen bonds observed by NMR spectroscopy.

Cyclic hexapeptides based on 47 were examined with shuffled N-methyl amino acids and inverted stereochemistries. Correlations between amide NH NMR temperature coefficients, Caco-2 and PAMPA permeability led to cyclic hexapeptide 57 (Figure 28). Compared to 47, 57 had one less N-methyl group and a modified N-methylation pattern but was still orally bioavailable in rats (1 mg/kg iv: CL = 55 mL/ min·kg, VD = 1.1 L/kg, t1/2 = 29 min; 10 mg/kg p.o.: AUC = 1003 ng·h/mL, Cmax = 117 ng/mL, F = 33%).141 Peptide 47 was thought to be orally bioavailable due to cyclosporin-like conformational flexibility; however, it showed no conformational difference in polar versus nonpolar

Figure 27. Peptoid substituted analogues 52−54 and β-hydroxy-γamino acid analogue 55. 52: MW = 741; miLogP = 3.5; HBD = 3; HBA = 13; RotB = 10; tPSA = 160 Å2; 53: MW = 727; miLogP = 3.6; HBD = 3; HBA = 13; RotB = 10; tPSA = 160 Å2; 54: MW = 713; miLogP = 3.6; HBD = 3; HBA = 13; RotB = 10; tPSA = 160 Å2; 55: MW = 793; miLogP = 3.6; HBD = 4; HBA = 14; RotB = 10; tPSA = 180 Å2. Dotted lines indicate conserved hydrogen bonds observed by NMR spectroscopy. 8106


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solvents.161 Several analogues of 47 were synthesized and their pharmacokinetic properties characterized to investigate conformational flexibility versus rigidity. The structure of 47 was rigidified by introducing a proline (58, Figure 29) or relaxed by introducing N-methylleucine (59, Figure 29). Both cyclic hexapeptides 58 (1 mg/kg iv: CL = 11 mL/min·kg, t1/2 = 58 min; 10 mg/kg p.o.: AUC = 4320 ng·h/mL, Cmax = 879 ng/mL, F = 30%) and 59 (1 mg/kg iv: CL = 10 mL/min·kg, t1/2 = 121 min; 10 mg/kg p.o.: AUC = 3713 ng·h/mL, Cmax = 768 ng·mL, F = 18%) were appreciably orally bioavailable in rats.161 For these compounds (59, 47, and 58) with identical HBD, HBA, and tPSA (Figure 29), reducing the MW (785 > 755 > 725), the number of rotatable bonds (12 > 10 > 8), and the hydrophilic surface area (FISA 127.5 > 122.5 > 110.4 Å2) all improved oral bioavailability (F% = 18−16 (28155) < 30, under the same conditions161). These changes had little effect on the overall structure of the macrocycle, as shown by NMR spectroscopy in CDCl3 and DMSO-d6, with two rigidifying antiparallel β-sheets connected by type 1 β-turns at each end (dotted lines, Figure 29).

Figure 30. Cyclic cell-penetrating hexapeptide (60). MW = 969; miLogP = −2.9; HBD = 22; HBA = 24; RotB = 24; tPSA = 422 Å2.

absorption. Preclinical toxicity studies determined LD50 in rats at 0.38−0.60 mg/kg iv.169

Figure 31. Kahalalide F (61). MW = 1492; miLogP = 3.0; HBD = 15; HBA = 30; RotB = 34; tPSA = 442 Å2. Figure 29. Derivatives of 47 with increased (58, left) or decreased (59, right) rigidity. 58: MW = 725; miLogP = 2.8; HBD = 3; HBA = 13; RotB = 8; tPSA = 160 Å2. 59: MW = 785; miLogP = 5.3; HBD = 3; HBA = 13; RotB = 12; tPSA = 160 Å2. Dotted lines indicate conserved hydrogen bonds observed by NMR spectroscopy.

5. CYCLIC HEPTAPEPTIDES 5.1. Sanguinamide A and Danamides

Sanguinamide A (62, Figure 32) is a thiazole-containing cyclic heptapeptide isolated from H. sanguineus.170 It has six natural Lamino acids including two prolines that adopt a cis, trans configuration, and an isoleucine-derived thiazole.171 No biological activity is known for sanguinamide A, but it is orally bioavailable in rats (1 mg/kg iv in DMSO: t1/2 = 23 min, CL = 70 mL/min; 10 mg/kg p.o.: Tmax = 60 min, Cmax = 40 nM, F = 7 ± 4%).171 The three-dimensional structure helped rationalize the pharmacokinetic profile of 62. Two amide protons formed intramolecular hydrogen bonds and were shielded from solvent by bulky side chains, while two prolines and thiazole removed 3 amide NH protons, lowering the HBD count. NMR studies on analogues of 62 examined H-D exchange rates and amide temperature coefficients and determined NMR solution structures in d6-DMSO. These data guided introduction of the bulky tert-butylglycine to minimize solvent exposed polarity, resulting in danamide D (63, Figure 32) that was orally bioavailable (1 mg/kg iv in DMSO: CL = 12.5 mL/min·kg, t1/2 = 65 min; 10 mg/kg p.o. in olive oil: Cmax = 352 ng/mL, Tmax = 240 min, AUC = 2647 ng·h/mL, F = 21 ± 2%). When an Nmethyl group was removed (danamide F, 64, Figure 32), even better oral bioavailability was obtained (1 mg/kg iv in DMSO: CL = 23.0 mL/min kg, t1/2 = 97 min; 10 mg/kg p.o. in olive oil: Cmax = 726 ng/mL, Tmax = 240 min, AUC = 3372 ng·h/mL, F = 51 ± 9%). This result highlighted the point that N-methylation of solvent accessible amides does not necessarily always improve oral bioavailability.172

4.11. Cyclo-[Arg-Arg-Arg-Arg-NaphthylAla-Phe]

Cell penetrating peptides (CPPs) are a small group of short, natural and synthetic, peptides that are often arginine rich, positively charged, amphiphilic, and able to cross cell membranes. How they cross membranes is still not fully resolved but mechanisms include endocytosis and direct translocation across the membrane.162−164 A series of arginine-rich, cell-penetrating, cyclic hexapeptides were synthesized, and their cellular uptake was measured. One analogue, cyclic hexapeptide 60 (Figure 30), was orally administered to mice and pharmacokinetic parameters were measured (1.5 mg/ kg iv: Cmax = 12174 nmol/L, t1/2 = 1.02 h, CL = 0.08 mL/min, VD = 7.51 mL; 40 mg/kg p.o.: Cmax = 3156 nmol/L, AUC = 6357 nmol/L, F = 4%) showing it had some oral bioavailability.165 4.12. Kahalalide F

Kahalalide F (61, Figure 31) is the largest depsipeptide in the family of kahalalides (A-F) and was isolated from the sacoglossan mollusk E. rufescens and the green alga Bryopsis.166 Compound 61 induced oncosis in human prostate and breast cancer cells.167 Pharmacokinetic parameters were measured in Phase I clinical trials (iv: t1/2 = 0.47 h, CL = 11.0 L/h, VD = 7.0 L).168 Kahalalide F had LD50 of 300, 980, and 3200 mg/kg p.o. in mouse, rat, and rabbit, respectively, suggesting very low oral 8107


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lethal dose (LD100 = 65 mg/kg ip). Distribution studies in mice177 indicated uptake from the small intestine with concentration in the liver, lung, and heart.

Figure 32. Sanguinamide A 62 (R1 = H, R2 = Me), danamide D 63 (R1 = Me, R2 = tBu), and danamide F 64 (R1 = H, R2 = tBu). 62: MW = 722; miLogP = 2.0; HBD = 4; HBA = 13; RotB = 6; tPSA = 170 Å2. 63: MW = 778; miLogP = 3.6; HBD = 3; HBA = 13; RotB = 7; tPSA = 161 Å2. 64: MW = 764; miLogP = 3.3; HBD = 4; HBA = 13; RotB = 7; tPSA = 170 Å2. Dotted lines represent hydrogen bonds as determined by NMR spectroscopy.171

Figure 34. Microcystin-LR (66). MW = 995; miLogP = −3.5; HBD = 12; HBA = 22; RotB = 16; tPSA = 341 Å2.

5.4. YM254890

YM254890 (67, Figure 35) is a specific Gαq/11 inhibitor produced by an isolate of the chromobacterium sp. QS3666. The structure is a depsipeptide with 2 ester linkages and a Dphenylalanine derivative. Gαq/11, a G protein implicated in purine nucleotide-induced platelet aggregation, was inhibited by 67 by targeting the transformation of GDP to GTP. In rats, 67 inhibited ex vivo platelet aggregation and in vitro thrombus formation, suggesting it may lead to a new antithrombotic agent. It has been used orally to treat mice with acute thrombosis and chronic neointima formation after induced vascular injury. Internal bleeding in mice was also effectively treated with 67 at 0.03 mg/kg iv or 1 mg/kg p.o., indicating an oral absorption < 3%.178

5.2. Rhizonin A

Rhizonin A (65, Figure 33) is cyclo-[N(Me)Ala-N(Me)DAla(fur-3-yl)-D-aIle-D-Val-Val-N(Me)Ala(fur-3-yl)-Leu]. It was isolated from fungi R. microspores, a known infection in fruits, vegetables and malt products. This cyclic heptapeptide consists of L- and D-amino acids, three N-methyl amides and two (2furyl)-alanines in both (R)- and (S)-configurations.173 In crystals of 65 grown from ethyl acetate/hexane, the four bulky side chains including three β-branched residues were at the wide end of the ovoid macrocycle. The other end showed a transannular hydrogen bond between the Ile NH and D(furylalanine)-carbonyl oxygen.173 Rhizonin A 65 was given orally to male albino rats (70, 96, 131, or 180 mg/kg p.o.) to determine the oral LD50. The lowest dose exceeded LD100 as all rats died within 10 days.174 There was no data for iv administration, so oral bioavailability could not be quantified.

Figure 35. YM254890 (67). MW = 960; miLogP = −0.2; HBD = 5; HBA = 22; RotB = 13; tPSA = 288 Å2.

Figure 33. Rhizonin A (65). MW = 812; miLogP = 2.6; HBD = 4; HBA = 16; RotB = 10; tPSA = 204 Å2. Dotted line represents hydrogen bond observed in crystal structure.

5.5. CHEC-7

CHEC refers to a series of peptides of various sizes derived from the natural survival anti-inflammatory protein dermicidin. CHEC-7 (68, Figure 36) reduced the incidence of experimental autoimmune encephalomyelitis in a disease model when administered to rats (1.5 mg/kg p.o. or 0.1 mg/kg/day sc).179

5.3. Microcystin LR

Microcystin-LR (66, Figure 34) from M. aeruginosa is one of the most toxic of over 80 microcystins produced by cyanobacteria in aquatic environments. Its amino acid sequence is D-alanine, L-leucine, D-methylaspartic acid, variable L-amino acid, a 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6dienoic acid (Adda), D-glutamic acid, and N-methyldehydroalanine. The extensively modified cyclic peptide is highly watersoluble and a persistent contaminant that accumulates in fish and displays effects on their liver, gastrointestinal tract, and kidneys.175 Acute hepatotoxic effects especially apoptotic hepatocyte death were observed in mice,176 although the oral toxic dose (LD50 = 11 mg/kg p.o.) is ∼170 fold lower than the

5.6. Polymyxin B1 and B2

Polymyxin B (Figure 37) is a mixture of two natural product cyclic peptides, polymyxin B1 69 and B2 70, containing multiple unusual diaminobutyric acids and a D-Phe residue. Prolonged treatment with polymyxin B mixture could not neutralize lipooligosaccharide-induced immune cell activity in mice. However, modulation of this response was observed by oral administration in drinking water (29.5 mg/L p.o. suspension in water).180 Human patients with liver disease have been treated with enteric coated oral polymyxin B. Plasma endotoxin and 8108


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Figure 36. CHEC7 (68). MW = 759; miLogP = −5.6; HBD = 3; HBA = 21; RotB = 9; tPSA = 347 Å2.

Figure 38. Bacitracin A (71). MW = 1437; miLogP = −1.8; HBD = 20; HBA = 33; RotB = 32; tPSA = 531 Å2.

ammonia levels were reduced, even though polymyxin B itself could not be detected above 0.5 units/mL.181

inhabited the gut of the test animals. Further work on analogues of 72 in chickens suggested that certain functional groups, lipophilicity, and PSA influenced anthelmintic activity in vivo.191

Figure 37. Polymyxin B1 (69) and B2 (70). 69: MW = 1189; miLogP = −5.6; HBD = 23; HBA = 29; RotB = 28; tPSA = 491 Å2. 70: MW = 1203; miLogP = −5.5; HBD = 23; HBA = 29; RotB = 29; tPSA = 160 Å2.

Figure 39. PF1022A (72) and emodepside (73). 72: MW = 949; miLogP = 7.9; HBD = 0; HBA = 16; RotB = 12; tPSA = 186 Å2. 73: MW = 1119; miLogP = 7.8; HBD = 0; HBA = 20; RotB = 14; tPSA = 211 Å2.

5.7. Bacitracin A

Bacitracin A (71, Figure 38) is a cyclic thiazoline-containing peptide from a family of cyclic peptides isolated from the “Tracy I” strain of B. subtilis. Bacitracins are an intriguing group of non-ribosomal peptides containing a sequence of alternating L - and D-amino acids. Bacitracin A was compared to vancomycin for treating antibiotic-associated diarrhoea. Plasma and urine concentrations were measured to quantify unwanted systemic absorption. 71 was found in plasma at low non-toxic concentrations after oral administration.182 Another study in which 71 was administered orally to dogs found significant levels in blood and urine, confirming absorption from the intestinal tract.183 Bacitracin A has been investigated for the treatment of vancomycin-resistant E. faecium in humans. In combination with doxycycline, 71 was not efficacious beyond the 2-week interval during which they were given.184 71 has oral toxicity in mice (LD50 > 3750 mg/kg p.o.).185

Emodepside (BY 44-4400, 73, Figure 39), a dimorpholine derivative of 72, has been approved for use in animals. Four different crystal forms have been reported from methanol.192 With no possibility of forming transannular hydrogen bonds, the carbonyl groups are directed above and below the plane of the macrocycle and are highly solvent exposed, one D-lactate side chain occupying the interior (CCDC code: DOMZOW). Compound 73 was orally active against nematodes and orally bioavailable (F = 47−54%). It had a long elimination half-life following intravenous administration to rats (t1/2 = 39−51 h).189,190 A phase I clinical trial investigating oral dosing of 73 in normal healthy male volunteers is ongoing.193 6.2. WH1Fungin

WH1Fungin (74, Figure 40) is a surfactin type lipodepsipeptide extracted from B. amyloliquefaciens WH1. As an immunoadjuvant, 74 was orally active in mice (0.2 mg) and enhanced the immune response to coadministered protein antigens (chicken ovalbumin or glutathione S-transferase).194 74 was also shown to reduce blood glucose and increase serum insulin in non-obese diabetic mice following oral administration at two doses (5 or 25 mg/kg p.o. in 100 μL PBS).195

6. CYCLIC OCTAPEPTIDES 6.1. PF1022A and Emodepside

PF1022A (72, Figure 39) is a cyclic octapeptide natural product with anthelmintic activity first isolated in 1992 from the fungus M. sterilia. It contains four N-methyl-L-leucine residues alternating with D-lactic acid or D-phenyllactic acid. PF1022A (72) was orally active (0.5−2.0 mg/kg p.o.) and effective against A. galli nematode (ring worm) infections in chickens (0.5−2.0 mg/kg p.o.)186 and nematode infections in rats (5 or 10 mg/kg p.o.),187 sheep (1 mg/kg p.o.),188 and other species.189,190 These data gave no insights into intestinal absorption of 72 following oral dosing, since the nematodes

6.3. α-Amanitin

The poisonous mushrooms of the Amanita genus contain a number of related constrained cyclic peptides of MW = 770920. These are toxic after ingestion and include phallotoxins, amatoxins, and virotoxins.196,197 Some of these toxins are heat stable and are not destroyed by cooking. Phallotoxins from A. 8109


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Figure 40. WH1Fungin (74). MW = 1064; miLogP = 8.0; HBD = 9; HBA = 20; RotB = 27; tPSA = 345 Å2. Figure 41. α-Amanitin (75). MW = 889; miLogP = −4.1; HBD = 13; HBA = 23; RotB = 7; tPSA = 361 Å2.

phalloides are bicyclic heptapeptides, amatoxins (A. phalloides) are bicyclic octapeptides, and virotoxins (A. virosa) are monocyclic heptapeptides.198 Despite extensive modifications (e.g., leucine, proline hydroxylation, D-configuration, thia-crosslink) these are ribosomally generated peptides.199 A systematic examination of their oral absorption has not been carried out but they display high toxicity. α-Amanitin (75, Figure 41) is a member of the group of poisonous peptides called amatoxins; all L-configured bicyclic octapeptides found in Amanita species of mushrooms. Amatoxins contain an oxidized tryptathionine linkage in addition to backbone cyclization. Multiple crystal structures (PDB codes: 1K83, 2VUM, and 3CQZ)200−202 of α-amanitin (75) bound to RNA polymerase II showed, in addition to six hydrogen bonding interactions to the enzyme, two transannular hydrogen bonds and two more describing β-turns within the αamanitin framework. Although native unbound α-amanitin crystal structures are not available, simple OMe and sulfone analogues (CCDC entries CAZFIS, CAZFIS10, CAZFOY, CAZFOY10) show similar structures to the protein bound forms above, with two β-turns, one transannular hydrogen bond is lost in the free form.203,204 Interestingly, it appears that the toxicity of the amanitins can be modulated by the degree and stereochemistry of oxidation at the bridging sulfur, with the sulfone analogues being the most toxic, while retaining nearly all structural features of the peptidic backbone. α-Amanitin causes severe liver damage and in some cases death (50−100 fatalities per year in Europe) through acute liver failure.205 75 is orally active only in certain species. The lethal oral dose in humans has been estimated at 0.1 mg/kg from accidental deaths. In guinea pigs, identical toxicity following oral, intravenous and intraperitoneal administration (LD50 = 0.1 mg/kg) indicated good intestinal absorption. By contrast, toxicity in mice (LD50 = 0.4−0.8 mg/kg iv) and rats (LD50 = 3.5−4.0 mg/kg iv) is only observed following iv administration. Cats and dogs absorb amatoxins following oral administration, but the absorption rate is slow. In dogs, the toxic oral dose is five times higher than the toxic intravenous dose (LD50 = 0.5 mg/kg p.o. vs 0.1 mg/kg iv). In cats, the toxic oral dose was more than ten times higher than the toxic intravenous dose.206

Pharmacokinetics were improved by simple structural modifications. Griselimycin contains an N-methyl-D-leucine, one proline, and two 4-methylproline residues. Modification of the 4-position of proline gave methyl-griselimycin 77 (3 mg/kg iv: CL = 35 mL/min·kg, VD = 1.6 L/kg, t1/2 = 144 min; 30 = mg/ kg p.o.: AUC = 6600 ng·h/mL, Cmax = 2820 ng/mL, F = 47%), dimethyl-griselimycin 78 (3 mg/kg iv: t1/2 = 132 min; 30 mg/ kg p.o.: AUC = 17000 ng·h/mL, Cmax = 4570 ng/mL, F = 59%), (S)-fluoro-griselimycin 79 (3 mg/kg iv: t1/2 = 120 min; 30 mg/kg p.o.: AUC = 5100 ng·h/mL, Cmax = 1490 ng/mL, F = 55%), and cyclohexyl-griselimycin 80 (3 mg/kg iv: CL = 18.3 mL/min·kg, VD = 5.5 L/kg, t1/2 = 258 min; 30 mg/kg p.o.: AUC = 23000 ng·h/mL, Cmax = 2620 ng/mL, F = 89%); all apparently with improved oral bioavailability and pharmacokinetic properties.208 Griselimycin and the cyclohexyl analogue 80 have each been crystallized in complex with the sliding clamp of Mycobacterium tuberculosis (PDB code: 5AH2, 5AGU, 5AH4, and 5AGV).208 The bound griselimycins showed two internal hydrogen bonds, one γ-turn from the Leu CO preceding MePro to the Leu NH after it, one transannular hydrogen bond between the Gly NH and the N-Me-Leu carbonyl group, and one transannular hydrogen bond between the Gly NH and the N-Me-Leu carbonyl group. 6.5. Dihydromycoplanecin and Mycoplanecin

Dihydromycoplanecin A (81, Figure 43) was discovered as an active metabolite in the urine of dogs and mice treated with the antibiotic mycoplanecin A (82, Figure 43). Both 81 and 82 are cyclized through a depsipeptide linkage between the Cterminus and a threonine residue. Further modifications include four N-methylated amides, 4-methyl and 4-ethylsubstituted prolines, L-homoleucine and α-hydroxy (81) or α-ketobutanoyl (82) N-terminal caps. No oral pharmacokinetic data has been reported for 82, but oral toxicity has been reported (LD50 > 3 g/kg p.o.).210 Pharmacokinetic parameters for 81 have been measured in mice (t1/2 = 0.5 h; 50 mg/kg p.o.: Cmax = 10 μg/ mL at 2 and 4 h) and dogs (t1/2 = 5.5 h; 25 mg/kg p.o.: Cmax = 9 μg/mL at 3 h; 12.5 mg/kg p.o.: Cmax = 5 μg/mL at 3 h). Quantification of 81 from urine led to estimates of F = 21% in mice and 22−25% in dogs.211

6.4. Griselimycin and Synthetic Derivatives

Griselimycin (76, Figure 42) is a macrocyclic poly-Nmethylated depsipeptide isolated from Streptomyces bacteria cultures.207 Griselimycin derivatives exhibit antibiotic activity, oral bioavailability, metabolic stability, and antitubercular activity.208,209 Griselimycin has impressive pharmacokinetics for its chemical class and size (3 mg/kg iv: CL = 40 mL/min· kg, VD = 1.2 L/kg, t1/2 = 120 min; 30 = mg/kg p.o.: AUC = 5100 ng·h/mL, C max = 3900 ng/mL, F = 48%). 208

7. CYCLIC NONA- AND DECA-PEPTIDES 7.1. CHEC-9

Disulfide-cyclized nonapeptide CHEC-9 (83, Figure 44) is a putative inhibitor of Heat Shock Protein 70 and secreted phospholipase A2. Following oral administration to rats (1 mg/ kg p.o. in gelatin solution) it was found in cytosolic fractions of 8110


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7.2. AFPep

AFPep (84, Figure 45) is a cyclic analogue of the 472−479 fragment from alpha-fetoprotein (AFP). AFP inhibits estrogenstimulated growth of immature mouse uterus and estrogendependent proliferation of human breast cancer cells.213 The linear peptide fragment has a bench life of a few weeks and an undesirable biphasic dose−response curve. Cyclization, substitution of proline for hydroxyproline, and addition of asparagine to the C-terminus gave AFPep (84).214 AFPep was orally active and arrested growth of human tumor xenografts in mice (10 μg/mouse p.o.). It also decreased the incidence and multiplicity of breast cancers in carcinogenexposed rats (100 μg/rat p.o.). In these animal models, AFPep had similar effects when administered via oral, ip or sc routes.215,216 Figure 42. Natural product griselimycin (76, R1 = R2 = H) and synthetic derivatives: methyl-griselimycin (77, R1 = Me, R2 = H), dimethyl-griselimycin (78, R1 = R2 = Me), (S)-fluoro-griselimycin (79, R1 = F, R2 = H), and cyclohexyl-griselimycin (80, R1 = cyclohexyl, R2 = H). 76: MW = 1113; miLogP = 4.3; HBD = 3; HBA = 22; RotB = 12; tPSA = 256 Å2. 77: MW = 1127; miLogP = 5.6; HBD = 3; HBA = 22; RotB = 12; tPSA = 256 Å2. 78: MW = 1142; miLogP = 5.1; HBD = 3; HBA = 22; RotB = 12; tPSA = 256 Å2. 79: MW = 1131; miLogP = 4.3; HBD = 3; HBA = 22; RotB = 12; tPSA = 256 Å2. 80: MW = 1196; miLogP = 7.5; HBD = 3; HBA = 22; RotB = 13; tPSA = 256 Å2.

Figure 45. AFP fragment 472−479: MW = 844; miLogP = −5.1; HBD = 12; HBA = 22; RotB = 23; tPSA = 350 Å2. AFPep (84): MW = 969; miLogP = −5.4; HBD = 17; HBA = 28; RotB = 13; tPSA = 455 Å2 .

Figure 43. Dihydromycoplanecin (81) and mycoplanecin (82). 81: MW = 1186; miLogP = 5.2; HBD = 4; HBA = 23; RotB = 16; tPSA = 276 Å2. 82: MW = 1184; miLogP = 5.0; HBD = 3; HBA = 23; RotB = 16; tPSA = 273 Å2.

7.3. Antamanide and Cyclolinopeptide

Antamanide (85, Figure 46) is a cyclic decapeptide derived from the same fungus as α-amanitin 75 (A. phalloides). Antamanide protects against phalloidin poisoning198 by blocking the organic anion transporting polypeptide mechanism. This inhibits the uptake of phalloidins into hepatocytes. Thus, antamanide functions by a mechanism similar to immunosuppressants cyclosporin A and FK506.217 A related hydrophobic cyclic nonapeptide cyclolinopeptide (86) found in linseed oil displayed immunosuppressive activity in a mouse model following oral administration (10 or 100 μg/mouse p.o. in olive oil).218 A crystal structure of 85 from acetonitrile/water (CCDC code: ANTAHC10) showed two transannular hydrogen bonds in a large bowl-shaped macrocycle. The concave face displayed most of the polar atoms, including all hydrogen bond donors. These NH groups were almost entirely shielded by the hydrophobic side chains.219 Two structures of 86 (CCDC codes: GIPKAR10, POWWEE) from isopropanol/water and methanol/water both showed three internal hydrogen bonds.220,221 One formed a β-turn around residues LIIL and two transannular interactions. A conserved water molecule was

the frontal cortex tissues. This indicated both oral absorption from the gut and blood-brain-barrier penetration,212 despite violating all RO5 and like parameters (Figure 44).

Figure 44. CHEC-9 (83). MW = 917; miLogP = −6.0; HBD = 16; HBA = 26; RotB = 10; tPSA = 425 Å2. 8111


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tightly held to a polar patch composed of 2 phenylalanine NH and two proline carbonyl oxygens.

Figure 48. Permetin A (88). MW = 1101; miLogP = −1.8; HBD = 16; HBA = 24; RotB = 18; tPSA = 386 Å2.

Figure 46. Antamanide (85) and cyclolinopeptide (86). 85: MW = 1147; miLogP = 2.4; HBD = 6; HBA = 20; RotB = 9; tPSA = 256 Å2. 86: MW = 1040; miLogP = 4.6; HBD = 7; HBA = 8; RotB = 13; tPSA = 244 Å2.

were modified. Their in vitro permeability, metabolic stability and other pharmacokinetic parameters were evaluated in rats (Table 1). These were the first examples of cyclic peptides of comparable size to cyclosporin A (109) with comparable or greater oral bioavailability.

7.4. Cyclopeptolide 1

7.7. Surotomycin

Cyclopeptolide 1 (87, Figure 47) is a cyclic 10-residue peptide featuring five N-methyl amides, a depsi-peptide, an O-methyl tyrosine, and a pipecolic acid. Isolated from the fungus Septoria sp., 87 was used to treat systemic and vaginal candidosis in rats by twice daily oral dosing for 4 days (8 × 200 mg/kg p.o.). A 90% cure rate was observed compared to 100% for the antifungal agent Ketoconazole.222

Surotomycin (CB-183315, 108, Figure 49) is a macrocyclic antimicrobial lipodepsipeptide, containing multiple unusual and D-amino acids. Originally from Cubist Pharmaceuticals, 88 was in development by Merck for treatment of C. dif f icile infections (CDI) and associated diarrhea. In hamsters, 108 was as effective as vancomycin when administered orally 12 h postinfection twice-daily for five consecutive days (2, 10, or 25 mg/kg p.o. in water).226 In clinical trials, orally administered 108 (125 and 250 mg p.o.) was safe and well tolerated in humans and proved more effective than vancomycin in the treatment of CDI.227 CDI occur in the gut, therefore low intestinal absorption and systemic availability is desirable. Low oral absorption was reported in rats (F < 1%)228 and pharmacokinetic parameters from clinical trials also indicated low systemic absorption in humans at various doses (500 mg p.o.: Cmax = 10.5 ng/mL, AUC0‑∞ = 317 ng h/mL; 4000 mg p.o.: Cmax = 86.7 ng/mL, AUC0‑∞ = 2572 ng h/mL).229

8. CYCLIC UNDECAPEPTIDES 8.1. Cyclosporin A and Synthetic Derivatives Figure 47. Cyclopeptolide 1 (87). MW = 1126; miLogP = 2.6; HBD = 4; HBA = 23; RotB = 12; tPSA = 282 Å2.

Cyclosporin A (Cyclosporine, CSA, 109, Figure 50) is an orally bioavailable cyclic peptide natural product with a D-Ala and a butenyl-methyl-L-threonine. It was first isolated from the fungus T. inf latum in the early 1970s by scientists at Sandoz (now Novartis). CSA is most often used in the clinic as an injectable immunosuppressive drug to combat organ transplant rejection, but it is also used as an oral treatment for graft versus host disease. It binds to cyclophilin in lymphocytes.230 CSA has interesting pharmacokinetics and is a rare example of a large cyclic peptide (11 residues, MW = 1202 Da) with appreciable oral bioavailability (F = 20−70% depending upon formulation and species; 22−29% in rat).106,231 CSA has been used as a model for developing peptides into orally deliverable drugs. The crystal structure of CSA from acetone, and the NMR solution structure determined in CDCl3, both show that it is stabilized by four intramolecular hydrogen bonds between the backbone amide NH and the backbone carbonyl oxygen atoms (CCDC code: DEKSAN).232 In polar solvents like methanol, CSA exists in at least four conformations, but it is insoluble in water. Co-crystallization of CSA with cyclophillin (PDB code:

7.5. Permetin A

The decadepsipeptide permetin A (88, Figure 48) has two Dresidues and an unusual β-hydroxyisoheptanoic acid moiety. It displayed broad antibacterial activity in vitro. LD50 was determined in mice (LD50 36 mg/kg ip; LD50 2100 mg/kg p.o.).223 From these data, the oral absorption of 88 can be estimated at around 1−2%. 7.6. Synthetic N-Methyl β-Strand Decapeptides

Guided by known permeable and orally bioavailable peptides, researchers from Novartis prepared a library of highly Nmethylated cyclic decapeptides (89−107, Table 1).224,225 NMR studies showed extensive and varied intramolecular hydrogen bonds. For 94, a crystal structure from dichloromethane/ heptane (CCDC code: ILOWAJ) showed two beta turns and 2 transannular hydrogen bonds.224 N-Methylation and stereochemical patterns were preserved while specific side chains 8112


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Table 1. Highly N-Methylated Model Cyclic Decapeptides

a

no.

AA 1 + 8

AA 2 + 7

AA 3 + 6

AA 4 + 9

AA 5 + 10

CLa

AUCb (iv/p.o.)

F%

MW

miLogP

HBD

HBA

RotB

tPSA (Å2)

89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107

L L L A L L L L L L L L L L L L L L L

L A L A A A A A F A A A A G L A+L A+D A+K A+T

L L L A L L L L L L L L L L G L L L L

a a G G f p p p p f l p p p p p p p p

A A P P P F A V A A F F+X F+T F F F F F F

66 64 121 56 5 7 30 43 4 5 1 5 16 10 21 7 12 8 3

256/69 277/28 144/4 377/5 4532/767 2206/1006 579/912 379/40 3673/608 5773/487 12368/491 3219/1317 12368/491 1490/322 723/214 2470/788 1192/32 1700/8 4354/728

27 10 3 1 18 46 130c 11 17 10 4 40 73 22 29 32 2 0 15

1047 963 1043 791 1139 1139 987 1043 1139 1115 1200 1140 1093 1111 1111 1181 1184 1197 1170

3.9 1.2 3.3 −4.4 4.3 4.3 1.4 2.9 4.3 4.2 6.8 3.1 2.2 4.6 3.6 5.6 3.5 3.8 3.7

4 4 4 4 4 4 4 4 4 4 4 4 5 4 4 4 5 6 5

20 20 20 20 20 20 20 20 20 20 20 21 21 20 20 20 22 21 21

12 8 12 0 12 12 8 10 12 12 16 12 11 12 12 14 14 16 13

238 238 238 288 238 238 238 238 238 238 238 251 258 238 238 238 276 264 258

Units = mL/min·kg. bUnits = nM·h. X= 3-pyridylalanine. cValue exceeds 100% but has no SD reported.224

Figure 50. Cyclosporin A (109) and KI-306 (110). 109: MW = 1203; miLogP = 3.6; HBD = 5; HBA = 23; RotB = 15; tPSA = 279 Å2. 110: MW = 1391; miLogP = 3.7 (mPEG not counted); HBD = 4; HBA = 29; RotB = 24; tPSA = 347 Å2.

Figure 49. Surotomycin (108). MW = 1681; miLogP = −4.6; HBD = 25; HBA = 43; RotB = 33; tPSA = 702 Å2.

1CWA) revealed a single bound conformation that differed from its unbound crystal state.233,234 NMR solution structures of the CSA-cyclophilin complex in aqueous solution, and 13C enriched CSA bound to cyclophilin, supported the unusual binding conformation (PDB codes 1CYA, 1CYB).235,236 When bound to cyclophilin, CSA was not stabilized by intramolecular hydrogen bonds. Instead, the four-amide protons were orientated toward the exterior of the macrocycle. The existence of multiple different conformers of CSA suggests that it has a flexible structure. This has been hypothesized to play an important role in its unusual passive membrane permeability and oral bioavailability, although this has not been proven. KI-306 110 (Figure 50) is a monomethoxypoly(ethylene glycol) modified CSA prodrug developed to improve water solubility relative to CSA. The oral bioavailability of 110 and CSA (Sandimmune Neoral solution) were compared in rats. PEG-modified 110 (7 mg/kg p.o.: AUC = 32.8 μg/mL·h, Cmax

= 1.8 μg/mL, Tmax = 1.43 h) had higher bioavailability than CSA (Sandimmune Neoral, 7 mg/kg p.o.: AUC = 21.4 μg/mL· h, Cmax = 1.1 μg/mL, Tmax = 2.6 h).237 NIM811 (111, Figure 51) is a CSA analogue modified at position 4 with N-methylisoleucine and a D-Ala at position 8, and has been investigated as a therapeutic agent for the treatment of hepatitis C. 111 suppresses hepatitis C virus replication but, unlike CSA, was not immunosuppressive. It was found to have similar oral bioavailability to CSA in mice (10 mg/kg p.o.: Cmax = 2.1 μg/mL, Tmax = 2−5 h, AUC0−24 = 23.7 μg/mL·h), rats (10 mg/kg p.o.: Cmax = 1.4 μg/mL, Tmax = 4−8 h, AUC0−24 = 13.1 μg/mL·h), dogs (20 mg/kg p.o.: Cmax = 5.2 μg/mL, Tmax = 1 h, AUC0−24 = 38.2 μg/mL·h), and monkeys (10 mg/kg p.o.: Cmax = 1.7 μg/mL, Tmax = 3−8 h, AUC0−24 = 11.3 μg/mL·h).238 8113


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Figure 51. NIM811 (111). MW = 1203; miLogP = 3.6; HBD = 5; HBA = 23; RotB = 15; tPSA = 279 Å2.

SCY-635 112 (Figure 52) is a CSA analogue recently developed as a potent inhibitor of hepatitis C virus RNA replication and showed oral bioavailability in rats (5 mg/kg p.o.: Cmax = 900 ng/mL, Tmax = 4.0 h, AUC0‑∞ = 13000 ng·h/ mL, t1/2 = 19.2 h, F = 23.1%) and monkeys (5 mg/kg p.o.: Cmax = 1810 ng/mL, Tmax = 2.0 h, AUC0‑∞ = 27900 ng·h/mL, t1/2 = 24.6 h, F = 17.7%).239 Alisporivir (also Debio-025, DEB025, UNIL025, 113, Figure 52) is an orally bioavailable CSA analogue with N-methyl-D-alanine at position 3 and N-ethylvaline at position 4.240 Alisporivir completed Phase I and II clinical trials as a HCV antiviral drug that blocks viral replication. It has excellent pharmacokinetic and safety profiles and significantly decreased viral load in HCV-infected patients (1200 mg/day p.o.: Cmax = 1052 ng/mL, Tmax = 2.0 h, AUC0−12h = 3858 ng·h/mL).241,242

Figure 53. THR-123 (114). MW = 1926; miLogP = −6.2; HBD = 35; HBA = 49; RotB = 42; tPSA = 833 Å2.

including 3 L-lactic acids and 3 D-alpha-hydroxyisovaleric acids. The 36-membered macrocycle is a potassium-selective ionophore (LD50 4 mg/kg p.o, rat).244 Unfortunately, there is little pharmacokinetic data available for most dodecapeptides. 9.1. Cerulide

The cyclic dodecadepsipeptide cerulide (115, Figure 54) contains seven L-residues, five D-residues, six depsipeptide bonds, and six peptide bonds. It is an emetic toxin (induces vomiting) produced by the bacteria B. cereus.245 Cerulide was administered (p.o. or ip) to the S. murinus rodents to test for emetic effects at doses from 2 to 32 μg/kg. The maximal oral dose (32 μg/kg p.o.) resulted in emesis in 5 of 5 test animals. 115 (50 μg/kg p.o.) in combination with 5-HT3 antagonist, ondansetron (iv), had no emetic effect. The authors concluded that cerulide caused emesis through central 5-HT3 receptor stimulation of the vagus afferent. Cerulide had ED50 12.9 μg/kg (p.o.) and 9.8 μg/kg (ip) for inducing emesis in S. murinus rodents.245 9.2. L-Phenylalanine-Dipicolinate Macrocycle

Figure 52. SCY-635 (112) and alisporivir (113). 112: MW = 1322; miLogP = 2.9; HBD = 6; HBA = 25; RotB = 19; tPSA = 302 Å2. 113: MW = 1217; miLogP = 3.8; HBD = 5; HBA = 23; RotB = 15; tPSA = 279 Å2.

A series of linear and macrocyclic L-phenylalanine-dipicolinic acid based compounds were synthesized and tested for antiinflammatory activity. Anti-inflammatory activity was evaluated by oral administration (7 mg/kg p.o.) to rats with carrageenan-

8.2. THR-123

The 16-residue disulfide-bridged cyclic peptide THR-123 (114, Figure 53) was designed to mimic a loop in the structure of human BMP7; a protein from the TGF-β superfamily that binds Alk2/3/6 and antagonizes TGF-β−mediated activity. The disulfide bridge stabilizes the conformation. Compound 114 was active against kidney fibrosis by inhibiting the Alk3 receptor after oral administration (5−15 mg/kg p.o.) to mice.243

9. CYCLIC DODECA- AND TRIDECAPEPTIDES There are a number of cyclic dodecapeptides that are orally active. One example is the antibiotic valinomycin, which contains 3 L-valines, 3 D-valines, 6 depsipeptide components

Figure 54. Cereulide (115). MW = 1153; miLog P = 6.6; HBD = 6; HBA = 24; RotB = 12; tPSA = 332 Å2. 8114


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induced paw edema. Two known nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and diclofenac, were used as controls. Compound 116 (Figure 55) caused 72% inhibition of paw inflammation compared to 82% and 61% for indomethacin and diclofenac.246

Figure 55. L-Phenylalanine-dipicolinic acid based macrocycle (116). MW = 1930; miLogP = 8.6; HBD = 12; HBA = 36; RotB = 16; tPSA = 505 Å2.

Figure 57. α-Conotoxin MII (118) and lipidated analogue (119). 118: MW = 1711; miLogP = −5.8; HBD = 27; HBA = 45; RotB = 21; tPSA = 718 Å2. 119: MW = 1837; miLogP = −4.6; HBD = 27; HBA = 45; RotB = 29; tPSA = 718 Å2.

10. CYCLIC TETRADECAPEPTIDES AND BEYOND

orally to rats (0.3 or 3.0 mg/kg p.o.) and produced significant dose-dependent relief of neuropathic pain.249

10.1. Conotoxins and Synthetic Derivatives

Linaclotide (117, Figure 56) is a 14-residue peptide toxin that is cyclized through three cysteine disulfide bridges. It is a treatment for irritable bowel syndrome with constipation and for chronic constipation. 117 was stable in simulated gastric fluid up to 3 h and was not hydrolyzed by pepsin. Following oral administration to rats, 117 was found in plasma despite minimal oral absorption (10 mg/kg p.o.: AUC0−6h = 19.7 ng·h/mL, F = 0.1%).247

Figure 58. Head-to-tail cyclized analogue of α-conotoxin Vc1.1 (120). MW = 2160; miLogP = −6.3; HBD = 32; HBA = 59; RotB = 21; tPSA = 909 Å2. Figure 56. Linaclotide (117). MW = 1527; miLogP = −5.7; HBD = 21; HBA = 36; RotB = 13; tPSA = 574 Å2.

10.2. Duramycin

α-Conotoxin MII (118) and lipidated analogue 119 (Figure 57) are 16-residue bis-disulfide bridged natural peptides that are orally absorbed. Following oral administration of 118 and a lipophilic analogue 119 (1 mg/kg p.o.) to male Sprague− Dawley rats, ∼6% of both peptides crossed the GI tract and were found in a variety of body tissues based on radioactive labeling.248 A head-to-tail cyclized analogue of α-conotoxin Vc1.1 (120, Figure 58) from the cone snail C. victoriae was administered

Duramycin (lancovutide, Moli1901, 121, Figure 59) is a highly cross-linked 19-residue peptide with three lanthione bridges and one lysoalanine bridge, all derived from L-cysteine. 121 was given to rats via pulmonary, intravenous or oral administration. Faeces, urine, blood and tissue were collected over a 7-day period. Analysis indicated minimal systemic availability following oral administration with almost 100% of the oral dose recovered from faeces. Nevertheless, 121 was detected in serum of rats 7 days after oral administration (231 mg/kg p.o.).250 8115


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Recently a lysine mutant of kalata B1, KB1[T20K] (124, Figure 60),254 was investigated in an experimental autoimmune encephalomyelitis model of multiple sclerosis. 124 was efficacious when administered orally to mice (10 or 20 mg/ kg p.o.) and impeded disease progression at 20 mg/kg p.o. compared to the control group dosed with an inactive kalata B1 derivative [V10K].255 10.4. Stapled α-Helix

SAH-gp41(626−662) (125) is a doubly stapled 37 residue peptide reported to be a stable α-helix and resistant to pepsin and chromtrypsin. The bridging residues are of normal Sconfiguration but possess an additional α-methyl group. When mice were given 125 by oral gavage (10 and 20 mg/ kg p.o.; Figure 61), it was found in plasma in a dose dependent manner (10 mg/kg p.o.: Cmax = 1.5 μg/mL; 20 mg/kg p.o.: 2.3 μg/mL). The nonstapled linear analogue was not detected in plasma after oral administration.257 We are not aware of any other similar helix-constrained peptide reported to show any significant oral absorption at all.

Figure 59. Duramycin (121). MW = 2013; miLogP = −6.1; HBD = 29; HBA = 48; RotB = 19; tPSA = 760 Å2.

10.3. Kalata B1 and Other Cyclotides

The cyclotides are a rapidly expanding family of cyclic peptides, which owe their stability to a remarkably conserved cyclic cysteine knot (CCK) motif. Cyclotides have a range of biological activities (e.g., antiviral, antitumor, antibacterial) and are actively being investigated for their potential in drug development.251 The prototypic cyclotide, kalata B1 (122, Figure 60) is a 29-residue peptide from the African medicinal plant O. af f inis. Kalata B1 is a uterotonic agent252 and by virtue of its knotted structure is chemically and enzymatically stable and can be made into tea by infusing its parent plant with boiling water. This tea is an indigenous medicinal agent used to accelerate childbirth by inducing uterine contractions. Recently, orally active peptidic bradykinin B1 receptor antagonists were grafted onto kalata B1 to replace the entire loop 6 unit.253 The grafted analogue CKB-KAL (123, Figure 60) was the most potent compound studied and inhibited acetic acid induced abdominal contraction (the writhing assay) after injection (1 mg/kg ip) or oral administration (10 mg/kg p.o.). Maximum inhibition was similar for both routes (49% ip and 42% p.o.).253 All the cysteine cross-links have L-stereochemistry.

Figure 61. HIV fusion inhibitor helical peptide SAH-gp41(626−666) (125). B = Norleucine, X = (S)-α-methyl(4-pentenyl)alanine. 125: MW = 4589; QPLogP = −23.1*; HBD = 72; HBA = 117; RotB = 132; tPSA* = 2173 Å2. “*”: Data calculated with QikProp256 due to structures exceeding Molinspiration maximum size.

11. INFLUENCES ON ORAL BIOAVAILABILITY Oral bioavailability is a specific term that indicates how much intact peptide can be measured in the circulation after oral ingestion. By definition this parameter is dictated not just by compound absorption through an intestinal membrane but also by compound stability, interactions, and metabolism before intestinal absorption as well as compound stability, metabolism, tissue distribution, and clearance after uptake. Most proteins and peptides simply do not get absorbed from the GI tract, and those that do are often rapidly metabolized, cleared, or distributed into tissues. Key problems for peptides are their high polarity and large polar surface area, large size, low membrane permeability, high clearance, and rapid metabolism. Cyclization of peptides frequently aids formation of intramolecular hydrogen bonds and orientation of side chains, properties that can help shield polar atoms from the solvent medium (water/lipid) and protect against proteolytic degradation, reduce flexibility, reduce polar surface area, and promote permeation through cell membranes. We describe 125 cyclic peptides above that are orally absorbed, orally active or have a measured oral bioavailability (F%). Physicochemical parameters traditionally associated with limits on oral bioavailability have been calculated here for each compound (see Figure legends). For cyclic peptides with reported oral bioavailability, we now plot key molecular properties, such as MW (Figure 62A), miLogP (Figure 62B), HBD (Figure 63A), HBA (Figure 63B, Figure 64), RotB (Figure 65A) and tPSA (Figure 65B), against F%.

Figure 60. Cyclotides kalata B1 (122), CKB-KAL (123), and KB1[T20K] (124). 122: MW = 2892; QPLogP = −15.8*; HBD = 42; HBA = 74; RotB = 23; tPSA* = 1207 Å2. 123: MW = 3135; QPLogP = −17.6*; HBD = 42; HBA = 77; RotB = 26; tPSA* = 1224 Å2. 124: MW = 2919; QPLogP = −16.6*; HBD = 43; HBA = 74; RotB = 26; tPSA* = 1212 Å2. “*”: Data calculated with QikProp256 due to structures exceeding Molinspiration maximum size. 8116


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Figure 62. Plots of oral bioavailability (F%) versus (A) molecular weight, and (B) octanol−water partition coefficient (miLogP), of orally absorbed cyclic peptides 2−117.

Figure 63. Plots of oral bioavailability (F%) versus (A) hydrogen bond donors (HBD) or (B) hydrogen bond acceptors (HBA), for orally absorbed cyclic peptides 12−112.

The plot of molecular weight versus oral bioavailability (Figure 62A) shows that cyclic peptides with molecular weights ranging from 500 to 1350 can have some oral bioavailability (F = 0.1−10%). Cyclic peptides with higher oral bioavailability clustered into two distinct MW ranges 700−800 and 1000− 1200, the latter possibly skewed by the high number of decapeptide- and cyclosporine-like cyclic peptides. It is encouraging that 14 cyclic peptides with MW = 500−850 (2, 8, 12, 19, 31, 39, 47, 49, 55, 57−59, 63, and 64) had > 10% oral bioavailability. A further 23 cyclic peptides (73, 76−81, 89, 90, 93−98, 100−104, 107, 109, and 112) with MW = 960− 1350 had ≥10% oral bioavailability. These data demonstrate that a higher MW (> 500) does not necessarily preclude oral bioavailability for cyclic peptides, even though it is important for most small molecules.17,64,65,123,124 Oral bioavailability for each cyclic peptide in this review was next plotted against the predicted octanol−water partition coefficient (miLogP) in Figure 62B. The calculated miLogP

value is one of the better predictors of octanol−water partition coefficients.258 The partition coefficient P (or distribution coefficient D) is a ratio of hydrophobicity : hydrophilicity and a measure of relative compound solubility in the two solvents. To be orally absorbed, a cyclic peptide must permeate intestinal membranes by partitioning into the lipid, but it must not be so lipophilic that it cannot partition out. The compromise for small molecule drugs is LogP = 0−5, with some support for the variation −0.4 to 5.6.259 Figure 62B shows that most cyclic peptides in this review with F ≥ 10% oral bioavailability also had miLogP 1−5 (e.g., 2, 12, 19, 31, 39, 47, 49, 57, 58, 63, 64, 76, 79, 89, 90, 93−98, 100−103, 107, 109, and 112). The extent of oral bioavailability did not correlate with miLogP within this range. Seven orally bioavailable (F > 10%) cyclic peptides (59, 73, 77, 78, 80, 81, and 104) had miLogP > 5. Eleven cyclic peptides with miLogP < 0 had measurable oral bioavailability but this was limited to F 8117


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with F ≥ 10% oral bioavailability, but two-thirds of the cyclic peptides now conform to conventional RO5 guidelines. We conclude that HBA count is somewhat important for oral bioavailability of cyclic peptides but not as restrictive as the HBD count. Rotatable bonds (RotB) reflect the degree of conformational flexibility in a molecule. RO5 compliant drug-like compounds typically have ≤ 10 rotatable bonds.17 However, care must be taken in the use of RotB itself, or as part of any prediction model for oral bioavailability. First, it is notable that strict RO5 rules describe any bond in a cycle of any ring size as being not rotatable. However, as cyclic peptide ring size increases, the energy required to rotate Φ/Ψ bonds within the macrocycle decreases, reducing the utility of this RotB metric. As observed above, from cyclic tetrapeptide 2 to cyclosporin A, solution structures and crystal structures can often differ greatly due to such rotations or ring flips. Second, studies in rats and humans have shown that the calculation method, therapeutic class of compounds, and desired F% all influence the acceptable number of RotB. In rats, certain therapeutic classes of drugs had acceptable F% with RotB > 12.261 Recently, a study on the oral bioavailability of 1014 molecules in humans found the RotB limit to be 13.262 Figure 65A shows that most of the cyclic peptides examined here with oral bioavailability had 6−16 rotatable bonds. Compounds 12 (RotB = 2, F = 16%) and 112 (RotB = 19, F = 23%) were outside this range. Twenty three compounds exceeded RotB ≤ 10; compounds 2, 19, 31, 93, 97, 98, and 107 had F > 10%, while 36, 73, 76, 77, 78, 79, 80, 81, 89, 94, 100, 101, 102, 103, 104, 109, and 112 had F ≥ 20%. This is consistent with a degree of conformational rigidity being favorable for oral bioavailability of cyclic peptides. The plot of topological polar surface area (tPSA) versus oral bioavailability (Figure 65B) indicated that large polar surfaces (tPSA > 300 Å 2) were a barrier to appreciable oral bioavailability (F > 10%), likely due to low absorption and high clearance. Fifteen of the smaller cyclic peptides with still large polar surfaces (tPSA 100−205) had F = ≥ 5% (2, 7, 12, 18−20, 31, 39, 47, 49, 55, 57, 62, 63, and 64) and three had F > 30% (39, 57, and 64). Twenty four compounds with tPSA 200−300 were still orally bioavailable with F ≥ 10% (8, 31, 73, 76−81, 89, 93−98, 100−104, 107, 109, and 112), and violate the prediction limit17 for most drug-like small molecules (tPSA < 140 Å2).

Figure 64. Plot of oral bioavailability (F%) versus hydrogen bond acceptors (HBA), where the amide nitrogen is not counted as a HBA atom, for orally absorbed cyclic peptides 12−112.

< 10% (7, 8, 21−25, 33, 34, 40, and 92). These data suggest that hydrophobicity (and lipophilicity) is likely an important contributor to oral bioavailability of these cyclic peptides. This data shows that this parameter is more accommodating for cyclic peptides (miLogP = 1−8) than it is for small molecules (LogP = 0−5). Two RO5 criteria that guide oral bioavailability of drug-like small molecules are the numbers of hydrogen bond donors (HBD) and acceptors (HBA). A small molecule is considered more likely to be orally bioavailable if it contains ≤ 5 HBD and ≤ 10 HBA,14−16 This implies that hydrogen bond donors are more detrimental to oral bioavailability. Figure 63A shows that cyclic peptides with 1−6 HBD are much more likely to be orally bioavailable than those with HBD > 6. A few compounds (19, 20, 31, and 112) with HBD = 6 had F = 9−25%, but all compounds with HBD > 6, except 8, (15%) had F ≤ 10%. If this data set is representative of all cyclic peptides, HBD does indeed limit oral bioavailability for this class of molecules. Figure 63B shows that all cyclic peptides examined had HBA > 10, and those with F > 50% had HBA = 12−22. Thus, almost all of the orally bioavailable cyclic peptides in this review apparently violate the RO5 limit on HBA (Figure 63B), a guideline developed from small molecule drugs. This suggests that optimizing cyclic peptides to reduce HBD, rather HBA, is more likely to improve oral bioavailability. However, Figure 63B uses the original definition of HBA,14,15 which was simply the total count of all nitrogen and oxygen atoms, irrespective of their actual hydrogen bond accepting properties. This is important because the amide nitrogen is not a hydrogen bond acceptor due to electron delocalization of the nitrogen lone pair, indeed protonation always occurs preferentially on the amide oxygen, not the nitrogen.260 Thus, if HBA alone is re-counted without amide nitrogens, the result changes dramatically (Figure 64). As shown, 24 of the cyclic peptides for which F ≥ 10% now have HBA ≤ 10 (e.g., 2, 7, 8, 12, 19, 31, 39, 47, 49, 55, 57−59, 63, 64, 89, 93, 95−98, and 102− 104). Only 12 cyclic peptides with F ≥ 10% now have HBA > 10 (e.g., 73, 76-81, 100, 101, 107, 109, and 112). Thus, the HBA count is still violated by one-third of the cyclic peptides

12. CONCLUSIONS AND FUTURE PROSPECTS This compilation is based on data on oral activity, oral absorption, and oral bioavailability for 125 cyclic peptides, composed of 4 to 37 amino acids and derivatives. It indicates that there are opportunities to expand the molecular weight range beyond the RO5 limit of small molecules (MW ≤ 500) for cyclic peptides and still obtain appreciable oral bioavailability. This is encouraging for therapeutic targeting of protein−protein interactions that may require modulators with larger surface areas. The cyclic peptides show great variation in the parameters (MW, HBD, HBA, LogP, RotB, and tPSA) conventionally associated with limiting oral bioavailability (F%) of drug-like molecules. Such parameters are of course all interdependent. As molecules get bigger, they either increase in the number of polar components (increasing HBD and HBA) or nonpolar components (increasing LogP), generally become more flexible (increasing RotB), and thus expose more of their surface area to water (tPSA) and membranes. The RO5 has been used very successfully to guide 8118


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development of orally bioavailable small molecule drugs over the past two decades. However, it is clear from Figures 62−65 that orally bioavailable cyclic peptides can violate all of these parameters, especially MW, tPSA, HBA, and, but not to the same extent, HBD, RotB, and LogP. Interestingly, Figures 62, 63, and 65 show this to be true for the four most orally bioavailable (F > 70%) cyclic peptides (39, 80, 95, and 101), which respectively had MW > 500 (724, 1196, 987, and 1079), HBA > 10 (12, 22, 20, and 21), and three had tPSA > 200 Å2 (140, 256, 238, and 258). On the other hand, all four compounds respectively had HBD ≤ 5 (0, 3, 4, and 5), three had RotB ≤ 12 (12, 13, 8, and 10), two had milogP < 5 (6.8, 7.5, 1.4, and 2.0) and, without counting amide nitrogens, two had HBA ≤ 10 (9, 12, 10, and 11). Further systematic evaluations of new orally bioavailable cyclic peptides with MW > 500 are needed to support these observations and better define limits of these parameters on oral bioavailability. This may better enable prediction and optimization of orally bioavailable cyclic peptides larger than 5 amino acids. The above data set supports current and new chemical strategies to enhance oral absorption. These include reducing HBD by removing backbone amide NH protons through substitution with N-alkyl groups, esters, ethers, or hydrocarbons; incorporating the nitrogen into a heterocycle; or substituting amides with other surrogates. Thus, cyclic hexapeptide 39 has 3 depsipeptide linkages, 3 NMe substituents, and no NH protons; cyclic octapeptide 80 has 1 depsipeptide linkage, 2 NMe substituents, 2 prolines, and 3 NH protons; while cyclic decapeptides 90 and 101 both have 6 NMe substituents and 4 NH protons. However, these approaches may not be a panacea to the problem of poor oral bioavailability. Biological activity is usually dependent on three-dimensional structure, and N-methylation or insertion of amide isosteres263 that reduce NH protons (HBD) can alter peptide structure, which may negatively impact function. For example, amide protons might be required for direct binding to a target or for maintaining the bioactive conformation through intramolecular hydrogen bonds. N-Methylation or amide isosteres can disrupt either or both of these properties. Intramolecular hydrogen bonds are often desirable because they reduce the exposed polar surface of a peptide. Introducing an amide isostere also normally requires additional synthetic steps, the value of which must be weighed up against potential pharmacokinetic benefits. Ester bonds are present in many naturally occurring cyclic depsipeptides and are thought to be evolutionary adaptions that facilitate permeability through biological membranes. Romidepsin 12, largazole 13, kahalalide F 61, and Gq inhibitor YM254890 67 are among many examples of depsipeptides that are active in mammalian cells and bind to intracellular targets, supporting this hypothesis. However, ester bonds are also unstable and readily hydrolyzed by esterases in cells and in vivo. Although esterification has been widely exploited for delivering carboxylic acids as prodrugs, ester substitution can also jeopardize in vivo stability. For example, orally bioavailable romidepsin 12, largazole 13 and kahalalide F 61 have very short half-lives at 37 °C (t1/2 = 6, 0.3, 28 min), probably due to poor in vivo stability of their cleavable ester moieties. In enniatin B1 39, every second amino acid linkage is a depsipeptide bond. It displays unusually high oral bioavailability (F = 91%), but also has a very short half-life (t1/2 = 9 min) leading to minimal exposure in plasma (AUC 25.3 ng.h/mL).

Figure 65. Plots of oral bioavailability (F%) versus: (A) rotatable bonds (RotB) or (B) topological polar surface area (tPSA), for orally absorbed cyclic peptides 12−112.

Two important considerations missing from the above analysis are three-dimensional polar surface area and metabolic stability. There were only a few reported three-dimensional structures for cyclic peptides in this review, but the effect of three-dimensional structure and conformational preference of cyclic peptides in water versus lipid membranes is very important. Three-dimensional structure can significantly change the solvent-exposed polar surface area. Large macrocycles might be folded through intramolecular hydrogen bonds that are shielded from solvent. This could produce much smaller exposed polar surface areas than suggested by tPSA calculations on 2D structures. Structural compression may enable larger cyclic peptides (MW) with more polar atoms (HBD/HBA) and larger tPSA (but low 3D-PSA) to be tolerated for oral absorption. Compaction or hydrophobic collapse is a dominant feature of protein folding that enables proteins to shield their hydrophobic residues in their interiors away from water. 8119


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Conversely, passive diffusion through a lipid membrane would be favored by the reverse effect, structural compression to shield polar residues in the interior of a cyclic peptide and expose outer hydrophobic substituents to lipid bilayers. Compact structures that undergo minimal change when going from water through a lipid membrane to water again should pay a lower entropy penalty to overcome this transition. Thus, rigidity may be more desirable than flexibility for oral bioavailability, although this brings an accompanying problem of lower aqueous solubility. The nature and extent of water solvation is likely to be a key consideration for oral absorption. Water molecules need to be stripped away from polar surfaces to facilitate uptake from the gut via passive diffusion or for interaction with proteins that promote active transport. Experimental determination and comparison of solvation energies can be very helpful for predicting oral absorption as well as solubility. The nature of amino acid substituents and the degree of flexibility in the macrocycle not only dictates solvation but also susceptibility to oxidative and degradative metabolism. Amino acid substituents and peptide backbone conformation also determine interactions with proteins, including transporters and efflux promoters, metabolizing enzymes, albumin, plasma, and cellular proteins. All of these factors contribute to oral bioavailability and need to be studied to better understand how metabolism and clearance, in addition to absorption, are affected by structural modifications to cyclic peptides. This collection of cyclic peptides has the potential to stimulate chemists to reach for new horizons in the design, synthesis, and application to humans of larger, biologically active, compounds including macrocycles. To date extensive research has focused on membrane and cell permeability of peptides and macrocycles but, as emphasized in this review, membrane permeability is only one of many contributors to oral bioavailability. More details on solvation, absorption, metabolism, tissue distribution, clearance and three-dimensional structures of cyclic peptides can provide a deeper understanding of how to better exploit the different factors that influence their oral bioavailability and their promise as new oral therapeutics.

peptides with Professor Fairlie. He conducted postdoctoral research in the same lab. In 2017, he is a postdoctoral fellow in Professor Meldal’s group at University of Copenhagen. Research interests are in pharmaceutical sciences, natural products, cyclic peptides, organic synthesis, and drug discovery. Nicholas E. Shepherd developed bioactive helical peptide mimics during his Ph.D. at the University of Queensland. As a postdoctoral researcher at the University of Tokyo, he identified novel bimetallic catalysts to enantioselectively synthesize pharmaceutically important chiral small molecules. As an ARC DECRA fellow at the University of Sydney, he used chemical tools to define the structural basis for R/ DNA-binding proteins and epigenetic multiprotein complex function. He is currently a senior research officer at the University of Queensland. Weijun Xu was a lecturer at the School of Chemical and Life Sciences (Singapore Polytechnic), an undergraduate (B.Sc. Hons. Biochemistry, 2006) and postgraduate of University of Queensland (Ph.D., 2013− 2016), where he is a research assistant. He was an International Postgraduate Research Scholar and University of Queensland Advantage Scholar with Professor Fairlie on computer-aided molecular modeling of protein−ligand and protein−protein interactions, involving discovery of ligands for GPCRs, proteases, enzymes, and other proteins involved in human immune systems. Andrew J. Lucke obtained a Ph.D. in organic chemistry at Griffith University, followed by postdoctoral research in the United Kingdom and Australia. He has published in organic, medicinal, physical, and macromolecular chemistry. His recent research has used molecular simulation techniques to model interactions between small organic molecules and large biomolecules. He is a molecular modeller at La Trobe University with interests in organic synthesis, medicinal chemistry (drug design and development), peptidomimetics, and protein molecular dynamics. Martin Stoermer obtained a B.Sc. Hons (1986) and Ph.D. (1991) from University of Sydney in organic synthesis and organometallic reaction mechanisms. He worked in drug design at the Centre for Drug Design and Development, University of Queensland (1991− 1995) and in the Institute for Molecular Bioscience since 2001 as a Senior Research Officer. He has also collaborated with the pharmaceutical industry while at the Technical University of Clausthal-Zellerfeld, Germany (1995−1996) and the Victorian College of Pharmacy, Monash University (1996−2000).

AUTHOR INFORMATION Corresponding Author

David Fairlie studied at Adelaide, Australian National, New South Wales, Stanford and Toronto Universities. At University of Queensland, he led the Chemistry Group in the Centre for Drug Design and Development and is Head of the IMB Division of Chemistry and Structural Biology. Interests are medicinal/organic chemistry, protein mimics, and modulators of GPCRs, PPIs and enzymes in inflammation, infection, neurodegeneration and cancer. He studies mechanisms of chemical, immunological and biological reactions, disease development, and drug action.

*Fax: +61-733462990. E-mail: [email protected]. ORCID

Martin J. Stoermer: 0000-0003-3445-2104 David P. Fairlie: 0000-0002-7856-8566 Present Address §

La Trobe Institute of Molecular Sciences, La Trobe University, Melbourne, VIC 3083, Australia. Notes

The authors declare no competing financial interest. Tables of physicochemical parameters, pharmacological parameters, formulation vehicles for compounds in this review can be provided upon request from the authors.

ACKNOWLEDGMENTS We acknowledge grants from the National Health and Medical Research Council (Senior Principal Research Fellowships 1027369 and 1117017 to D.P.F.) and the Australian Research Council (DP150104609, DP130100629, DP160104442, and CE140100011).

Biographies Daniel S. Nielsen obtained a B.Sc and M.Sc from the Faculty of Pharmaceutical Sciences at University of Copenhagen (2011). He received a University of Queensland International Ph.D. Scholarship (2012) and obtained a Ph.D. (2016) on orally bioavailable cyclic

ABBREVIATIONS AFP alpha-fetoprotein 8120


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Tmax TNBS tPSA VD

AFPep Aha Alk3 AUC

alpha-fetoprotein 472−479 cyclic analogue 6-aminohexanoic acid bone morphogenetic protein receptor, type IA area under the curve, the integral of the concentration time curve (0-∞ = after a single dose or τ,ss = at steady state) BBMV brush border membrane vesicles BMP7 bone morphogenic protein 7 CL clearance, the volume of plasma cleared of the drug per unit time CSA cyclosporin A Cmax peak serum concentration C5a complement factor 5a CDI C. dif f icile infection CCK cyclic cysteine knot CDCl3 deuterochloroform CYP cytochrome P450 enzyme Da Daltons DMSO dimethyl sulfoxide EtOH ethanol ED50 dose required to give 50% of the maximal response EM electron microscopy F% fraction of orally absorbed compound in plasma GI gastro-intestinal HCV hepatitis C virus HDAC Histone deacetylase HBA hydrogen bond acceptors HBD hydrogen bond donors H-D hydrogen−deuterium exchange HIV human immunodeficiency virus HCT116 human colon carcinoma cell line 116 5-HT3 5-hydroxytryptamine subtype 3 iv intravenous ip intraperitoneal LD50 dose required to kill 50% of the test population LD100 dose required to kill 100% of the test population MDCK Madin-Darby canine kidney cells MDCKII-LE Madin-Darby canine kidney cells−low efflux mg/kg milligrams per kilogram MC4R melanocortin 4 receptor Me methyl miLogP Molinspiration octanol−water coefficient α-MSH alpha-melanocyte stimulating hormone MW molecular weight NH amide proton NK2 neurokinin 2 NMR nuclear magnetic resonance N-Me N-methyl NSAIDs nonsteroidal anti-inflammatory drugs PAMPA parallel artificial membrane permeability assay PEG400 polyethylene glycol average molecular weight of 400 p.o. per oral RO5 rule-of-five RNA ribonucleic acid RotB rotatable bonds SAH stabilized α helix sc subcutaneous SLC15A1 solute carrier family 15 member 1 t1/2 half-life the time taken for drug concentration to decrease by half its original value TGF-beta transforming growth factor beta

time to reach the peak serum concentration trinitrobenzenesulfonic acid topological polar surface area volume of distribution, the apparent volume in which the drug is distributed at steady state

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