Glycomimetics versus Multivalent Glycoconjugates for the Design of

Dec 11, 2014 - Biography. Samy Cecioni graduated (Master degree in organic chemistry) from Université Claude Bernard Lyon 1 and concurrently received...
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Glycomimetics versus Multivalent Glycoconjugates for the Design of High Affinity Lectin Ligands Samy Cecioni,‡,† Anne Imberty,† and Sébastien Vidal*,‡ †

CERMAV, Université Grenoble Alpes and CNRS, BP 53, F-38041 Grenoble Cedex 9, France Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie, UMR 5246, Université Lyon 1 and CNRS, 43 Boulevard du 11 Novembre 1918, F-69622, Villeurbanne, France



4.3. Application to the Inhibition of Dendritic Cell-Specific Intercellular Adhesion Molecule3-Grabbing Nonintegrin (DC-SIGN) 5. Conclusion Author Information Corresponding Author Notes Biographies References

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CONTENTS 1. Introduction 2. Design of High Affinity Lectin Ligands 2.1. Carbohydrate−Lectin Interactions 2.1.1. Carbohydrates and the “Sugar Code” 2.1.2. Lectins Read the “Sugar Code” 2.1.3. Information Is Read through Noncovalent Interactions 2.2. Multivalency Further Increases the Complexity of Interactions 2.2.1. Multivalent Partners Can Interact through Different Mechanisms 2.2.2. The “Cluster Glycoside Effect” Is Not an Obscure Phenomenon 2.3. On the Importance of Developing Tools To Modulate Carbohydrate−Lectin Interactions 2.4. Analytical Techniques 2.4.1. Determination of Inhibitory Potency (HIA, ELLA, SPR) 2.4.2. Determination of Thermodynamics Parameters (ITC) 2.4.3. Determination of Structural Features (Xray, AFM, NMR) 3. Small Molecules as High Affinity Ligands of Lectins 3.1. Modified Sialosides and Interactions with Myelin Associated Glycoprotein (MAG) 3.2. Modified Fucosides and Glycoclusters and Interactions with Pseudomonas aeruginosa Lectin B (LecB or PA-IIL) 3.3. Modified Galactosides and LacNAc Derivatives and Their Interactions with Galectins 3.4. Application to the Cholera Toxin AB5 System 3.5. Application to FimH (E. coli) 4. Multivalent Glycoconjugates as High Affinity Ligands of Lectins 4.1. Application to the Shiga Toxin AB5 System 4.2. Application to the Pseudomonas aeruginosa Lectin A (LecA or PA-IL)

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1. INTRODUCTION One could certainly highlight a conceptual resemblance between social interactions as the basis of societies and civilizations and the ability of molecules to interact in a noncovalent fashion as one of the most fundamental requirements for the emergence of living biological systems. Interacting biomolecules form complex and dynamic information networks that can be understood thanks to thermodynamic and kinetics fundamental principles. The simplest way to represent such an interaction is to consider two biomolecules in dynamic association following Fisher’s lock−key concept, the resulting complex being more stable than the two separated biomolecules. The idea of multivalency can emerge if one considers that several “locks” can be connected together and interact with structures comprising several “keys”. It appears that all biological systems from viruses to mammals have evolved using both monovalent interaction as well as multivalent associations between multivalent ligands and multivalent receptors. While many fields of biochemical and molecular biology sciences increasingly acknowledge the importance of multivalent interactions, the field of glycobiology has recognized its crucial role in its early development.1−5 The relevance of carbohydrates in complex biological processes has been largely underestimated for years, while many carbohydrate-binding proteins (i.e., lectins) were identified and characterized as multivalent receptors through the association of several carbohydrate-binding modules (CBM). Carbohydrates and carbohydrate−lectin interactions are now being identified in numerous biological processes of prime importance including fertilization,6 adhesion and virulence of pathogens,7 and inflammatory response.8 Multivalent carbohydrates−lectin interactions have been studied either for fundamental understanding of nonpathologic processes (e.g., signal transduction9) or to study and fight pathogenic infections.

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Received: June 6, 2014

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monovalent ligands, and multivalency is largely invoked to explain their high affinity and selectivity in vivo.28 The high diversity of lectin structures and functions and the relatively low number of monosaccharidic bricks may, at first, appear contradictory. Also, most lectins were thought to have a relatively low affinity for their ligand, and many lectins do not display a strong selectivity for a single carbohydrate (several lectins can recognize both glucose and mannose terminal residues). Given that, how can specific information emerge, and how could we apprehend the concept of a sugar code? The answer first lays in the extreme diversification emerging from the formation of oligosaccharides.28 Indeed, lectins were very often studied in vitro with monosaccharides or “simple” oligosaccharides, and the identification of their “natural” and physiologically relevant ligand is extremely difficult. The specificity of lectin for more complex oligosaccharides if often greatly increased and the development of glycan arrays (i.e., Consortium for Functional Glycomics − CFG) is dramatically helping to determine which complex oligosaccharide is actually the best ligand for a given lectin. However, the screening of a large number of complex glycans still frequently highlights several ligands with significant affinity for a given lectin. A second aspect that is often neglected when considering the features of the “sugar code” is actually the multivalent presentation of these oligosaccharides. If glycan arrays allow one to determine the affinity and specificity of a lectin toward glycans presented on a densely packed surface, the importance of the ligands topological presentation in a biologically relevant environment and its impact on lectin specificity is still largely overlooked, mainly because of the extreme difficulty associated with controlling and assessing parameters such as density of ligands, flexibility, conformation, or impact of the anchor-protein. Therefore, a meaningful apprehension of the “sugar code” concept demands a rigorous understanding of the extreme diversity of complex glycans but also the multivalent presentation of these ligands in their biological context. 2.1.3. Information Is Read through Noncovalent Interactions. Given the nature of carbohydrates and the presence of multiple hydroxyl functional groups, the formation of a hydrogen-bond network (Figure 1) is absolutely crucial for selective recognition of sugars by lectins.29−31 This interaction is directional, and the alignment of participating atoms is a strong element toward the specificity of lectins. The energy of such an interaction is intermediate between van der Waals contacts and a covalent interaction. 32 Hydrogen bonds are crucial for

The synthesis of multivalent glycosylated architectures was therefore largely developed in the past decades10−18 and provided precious breakthroughs toward deciphering the “sugar code”19,20 in relation with the high complexity of oligosaccharides.21−23 Meanwhile, the influence of the multivalent core could be demonstrated in a few cases in which the topology of the multivalent glycosylated ligand would fit the geometry of the lectin.14 This Review is aimed at giving an overview of the numerous synthetic approaches for building glycomimetics and glycoclusters designed for high affinity binding by lectins of interest in human health. Selected examples related to neurologic diseases, cancer, and infection are described. Four selected cases (i.e., LecB, FimH, LecA, and DC-SIGN) will describe both glycomimetics and glycoclusters for the design of anti-infective drugs because these lectins are among the few examples for which both approaches have been investigated. For these specific targets, a comparison of the glycomimetics versus glycoclusters approach will be indicated. The large panel of molecules that are listed is an image of the strong scientific activity in this domain.

2. DESIGN OF HIGH AFFINITY LECTIN LIGANDS 2.1. Carbohydrate−Lectin Interactions

2.1.1. Carbohydrates and the “Sugar Code”. Structural, stereochemical, and conformational diversity of carbohydrates can be seen as elements of information. This information modulates the physicochemical properties of glycoproteins (e.g., stability, folding, flexibility), thus adjusting its function such as for post-translational modifications. Yet glycans present on proteins or lipids can also be apprehended in terms of readable information, a specific tag that would be added on one particular protein at a precise amino-acid residue and that can be read by interacting biomolecules to enable a specific biological process. The particular properties conferred to the glycoprotein by the carbohydrates, their better understanding with the growing interest from the scientific community, and also the improvement of techniques used for their study led to the postgenomic era known as “glycomics”24,25 and the concept of “sugar code”.19,20 2.1.2. Lectins Read the “Sugar Code”. Lectins and lectin domains can be defined as “proteins of non-immune origin, with no catalytic activity, which are able to reversibly bind carbohydrates”. The discovery of lectins in all living organisms highlights an old evolutionary onset, thus triggering an increasing interest regarding their roles. Even though plant lectins were the first identified, their functions are not really well-understood yet. They are mostly proposed to be involved in defense mechanisms against parasites, fungi, and predators and in nitrogen fixation through the plant-rhizobium symbiosis.26,27 On the other hand, lectins from pathogens such as bacterial and viral lectins are being identified as adhesion molecules promoting early attachment and biofilm formation of the pathogens to the host tissues. Several bacterial lectins are also recognized as virulence factors, such as toxins or secreted cytosoluble lectins, which largely contribute to the overall pathogenicity in the infectious process. If most of the lectins possess multimeric quaternary structures, the physiological relevance of this multivalent presentation of binding sites remains to be established for a significant number of them. However, it is very interesting to note that most of the identified functions rely on adhesion events, modulation, and regulation processes that can benefit from multivalent interactions. Lectins usually display poor affinities for their

Figure 1. Hydrogen-bond network (dashed lines) between 3′-sialyllactose (cyan) and Maackia amurensis leukoagglutinin (MAL green/ orange, PDB code 1DBN).31 B

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biochemical events because they allow a fast and dynamic association/dissociation at room temperature in physiological environment. When hydrophobic molecules interact with hydrated binding sites, an entropically favorable desolvation and establishment of

Figure 3. Ionic interaction between sialic acid (cyan) and one arginine residue (orange) of canine adenovirus CAV-2 fiber head (green/ orange) (PDB code 2WBV).42 Figure 2. Hydrophobic stacking between maltose (cyan) and both tyrosine and tryptophan residues (orange) from the maltodextrinbinding protein (green/orange) (PDB code 1ANF).41

hydrophobic stacking are often considered as the basis for the socalled hydrophobic interactions. Even though carbohydrates are hydrophilic molecules, they also frequently establish hydrophobic interactions with lectins. Indeed, the two faces (α and β) of the pyranose ring display hydrophobic C−H bonds.29,33 It is therefore quite common to observe “stacking” of these cycles with aromatic amino acids (Phe, Trp, Tyr) in the binding sites of lectins, and these interactions are a powerful source of discrimination toward different carbohydrates (Figure 2). Noteworthy, CH3 groups present in 6-deoxy or N-acetylated carbohydrates commonly make hydrophobic contacts with aromatic residues. An enthalpic origin has been suggested recently34 in opposition to the classical entropically driven explanation of the hydrophobic contacts. The nature of such an interaction is still under intense debate as to whether it would constitute an atypical hydrophobic interaction35 or multiple weak C−H···π interactions.36−38 These hydrophobic interactions are undoubtedly a very important feature of the stereospecific binding properties of lectins.39,40 Carbohydrates are generally neutral species, but some sugars (sialic, glucuronic and iduronic acids, aminosugars, alkylatedthiosugars) or modified-sugars (phosphorylated and sulfated sugars) can be either positively or negatively charged.29 Charged functional groups can give rise to additional contacts with lectins through ionic electrostatic interactions with charged residues (Figure 3). Metal ions chelating lectins are found in plant, bacterial, and animal lectins, but two situations must be distinguished. For many plant lectins, two metallic ions (Ca2+ and Mn2+) are coordinated in the vicinity of the binding site. If these metals are required for carbohydrate-binding activity by maintaining structural integrity of the lectin, they do not directly participate in binding sugars.43 On the other hand, numerous examples of metal ions directly involved in the binding with carbohydrates can be found in bacterial and animal lectins. Usually, the cation is chelated by amino acids and the oxygen atoms from carbohydrates’ hydroxyl groups. The metal ion can play a significant role in the stereospecific recognition of carbohydrates via the relative stereochemistry (cis or trans) of two adjacent hydroxyl groups (Figure 4). The remarkable high affinity of LecB from the opportunistic bacterium Pseudomonas aeruginosa was

Figure 4. Calcium-mediated interaction of a high mannose N-glycan (cyan) with the human DC-SIGN carbohydrate recognition domain (green/orange) (PDB code 2IT5).45

the first example of a lectin with two calcium atoms participating in the interaction with a monosaccharide.44 In this example, the two Ca2+ atoms in the binding sites interact with the three hydroxyls of a fucose molecule. Finally, water molecules have a crucial role in carbohydrate− lectin binding events both as solvation molecules and as a relay in the establishment of hydrogen-bonding network. Hydrogen bonding through an intermediate water molecule is indeed quite frequent, and such a relayed hydrogen bond has a comparable energy.30,46 The desolvation of water molecules from both binding sites and carbohydrates ligand is very favorable entropically and is commonly invoked as an important driving force for many biomolecular interactions.47 The combination of hydrogen bonding, hydrophobic contacts, metal-chelation, and ionic interactions possesses all of the energetic and geometrical features that allow a specific network of interactions as the basis for the reading of the stereochemical information carried by carbohydrates through the “sugar code”.19 2.2. Multivalency Further Increases the Complexity of Interactions

2.2.1. Multivalent Partners Can Interact through Different Mechanisms. While the fundamental concepts ruling a “classical” noncovalent interaction can be complex, the interaction between two monovalent species (ligand and receptor) to form a unique product allows a straightforward expression of the equilibrium and of the association constants. C

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When dealing with multivalent receptors (such as a multivalent lectin) in interaction with a multivalent ligand (such as a cell surface coated with glycoproteins), the complexity of the binding event is obviously greatly increased. One major problem is the existence of several microscopic equilibria that can give rise to the observed overall equilibrium,48 and the main issue is often the dynamic competition between different mechanisms of interaction. Considering natural multivalent ligands and receptors in their complex biological environment, the mechanism of interaction that actually occurs can yield different processes and biological responses.49,50 The n binding sites of a homomultimeric lectin can interact simultaneously with m ligands from a multiglycosylated molecule through a chelate association mechanism (Figure 5a).18,51 This mechanism is one of the most studied and can give rise to tremendous avidity effects (multivalency-driven increase of affinity). For example, several multimeric lectins (e.g., AB5 toxins, hemagglutinins) have their binding sites on a single face to interact with glycosylated cell surfaces. A second type of mechanism called receptor clustering (Figure 5b) is often encountered when monovalent lectins or ligands are anchored to the cell membrane. In the presence of a multivalent binding partner, receptors can diffuse through the dynamic lipid bilayer and become clustered by the multivalent ligand. The receptor clustering mechanism has been identified in the triggering of signal transduction events through the clustering of the intracellular domains of transmembranar proteins.52−56 Another common mechanism is known as the subsite association (Figure 5c) in which a second binding site with different affinity and specificity can associate with a heterobivalent ligand.57,58 Multivalent glycosylated structures interacting with monovalent lectin could also yield some affinity improvement through a simple higher density of ligands available in close proximity of the binding site and therefore statistical reassociation (Figure 5d).59 2.2.1.1. Aggregative Mechanisms. The different multivalent binding events can happen in an intramolecular or intermolecular fashion. Intermolecular mechanisms can yield aggregative binding that can trigger formation of large noncovalent polymer chains or three-dimensional networks. A small number of repeats and relatively short oligomers can remain flexible and soluble, while longer chains and cross-linked networks yield irreversible precipitation.60,61 Such macromolecular assemblies have been studied for several lectins, and X-ray diffraction data have confirmed linear (Figure 6, Type 1) structures of galectine-1 with synthetic divalent glycocluster in vitro.62 When the valency of the glycocluster increases, the resulting aggregative two- or threedimensional networks (Figure 6, Type 2) can appear, and they are often poorly soluble and could therefore undergo irreversible precipitation. Once again, X-ray diffraction provided confirmation of such networks using soybean agglutinin (SBA).63 Dam and co-workers have extensively studied these networks and demonstrated tremendous affinity enhancements between SBA and mucin of porcin origin.64 To explain such avidity, the authors have invoked a “binding and sliding” mechanism59 in which the observed higher affinity is explained by an overall decrease in microscopic dissociation kinetics.65 Similarly, varying the geometry of the scaffold was used for controlling the aggregation process for peanut agglutinin interacting with multivalent glycosides.66 Even if these networks have better been identified in vitro, they also have been attributed fundamental roles in vivo. For example, Baum and co-workers have shown that galectin-1 and CD45/ CD3 glycoproteins form homogeneous reticulated networks on

Figure 5. Nonaggregative mechanisms of interaction between multivalent ligands and multivalent receptors.

Figure 6. Multivalency-mediated cross-linking of multivalent lectins by multivalent ligands.

T-cell cell surfaces.67,68 These “glyco-lattices” have been suggested to participate in signal transduction (apoptosis) thanks to receptor clustering and the tyrosine phosphatase activity of the cytosolic domain of such glycoproteins. 2.2.1.2. Aggregative Chelate Models. The formation of chelate aggregative model has been directly confirmed by the use of atomic force microscopy (AFM) for a few cases.69,70 In particular, a tetragalactosylated 1,3-alternate calix[4]arene was designed as a multivalent ligand of LecA, a galactose specific lectin of Pseudomonas aeruginosa.71 The formation of highly organized 1D lectin filaments was observed using AFM (Figure 7), in perfect agreement with the hypothesized chelate aggregative model.72,73 Aggregative mechanisms are very interesting processes in vitro as well as biologically relevant processes in vivo, but the formation of large aggregates raises issues when studying multivalent interactions. Such precipitation events are often kinetically controlled irreversible processes, therefore strongly perturbing the equilibria between soluble species. When irreversible pathways compete with equilibrated ones, thermoD

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Figure 7. (Left) Proposed chelate aggregative model for the interaction of LecA from Pseudomonas aeruginosa and a tetravalent calixarene-based glycocluster.71 (Right) AFM observation of lectin filaments triggered by the glycocluster and model of the 1D-network from molecular modeling.72,73

Figure 8. Binding of a sugar within the binding site of a lectin can, conceptually, be considered as an ideal, perfectly adjusted multivalent interaction composed of multiple fundamental interactions.

of multivalency, ideally aiming at the introduction of useful predictive models. Unfortunately, given the high complexity of such interactions and the frequent coexistence of several mechanisms, no model has yet been proven generally useful in quantitatively predicting multivalency-driven affinity improvements.78 When considering a theoretical pentavalent chelate association between a glycocluster and a putative pentameric lectin (Figure 8, left), the overall interaction could be seen as a 1:1 interaction composed of five different binding events. Zooming in (Figure 8, right), it is then philosophically interesting to consider that the monosaccharide-binding site interaction is, itself, composed of several fundamental interactions such as hydrogen bonding and hydrophobic stacking. Therefore, would it make sense to apprehend such a standard interaction as a perfectly optimized architecture of multivalent fundamental binding events? The concepts used to describe multivalent interactions (effective concentration,79−83 translational, rotational, and conformational entropies,50,84−90 as well as statistical thermodynamics and the degeneracy of the association85,91,92) could indeed be considered as perfectly optimized in a scenario of monovalent interaction within the binding site. There is no doubt that the field needs a useful approach to predict and to help design the most efficient multivalent glycoclusters. Conceptually, the proposed metaphor suggests that the perfect multivalent interaction should, overall, look very

dynamic principles and models (such as Gibbs free energy equation) will not stand, and the depiction of the interaction is therefore greatly complicated.74,75 2.2.1.3. Distinction with Cooperativity. When dealing with higher-valency interactions, there is still a frequent confusion between the apparent improvement of affinity in interacting multivalent systems and genuine cooperativity. The term “cooperativity” was coined to illustrate that the binding of a molecule (multivalent or not) to a receptor can impact the affinity of a second binding site toward its ligand. This impact can be either positive or negative and typically arise from conformational, polarization, or steric changes induced by the first binding event. In multivalent carbohydrate interaction, the binding sites are mostly independent, and apparent overall changes in affinity do not rise from cooperative binding. A clarification on this topic was proposed to name the apparent cooperativity in multivalent binding events as chelate cooperativity, while the standard cooperativity, as observed in oxygen binding to hemoglobin, would be called allosteric cooperativity.76 2.2.2. The “Cluster Glycoside Effect” Is Not an Obscure Phenomenon. The observed affinity improvements in multivalent carbohydrate−lectin interactions have then been attributed to the so-called “cluster glycoside effect”.60,77 Several theoretical models have been built from standard thermodynamic and kinetic approaches to describe the observed “effects” E

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much like the monovalent binding of a carbohydrate. The different theories and our efforts to understand both multivalent and monovalent interactions using the same fundamental tools do not directly provide a novel approach in the design of efficient architectures, but they do tend to demystify these interactions and certainly pave the way toward predictive concepts. 2.3. On the Importance of Developing Tools To Modulate Carbohydrate−Lectin Interactions

Oligosaccharides are naturally displayed at the surface of cells by glycoproteins or glycolipids embedded in the lipid bilayer. The vicinity of each terminal epitope usually involved in the binding to multivalent lectins is required for the proper multivalent binding of several epitopes at once with lectin multimers or clusters of lectins, therefore leading to high avidities. In the growing field of lectinology, the design of synthetic ligands is strongly driven by the hypothesis under scrutiny. If an antiadhesive approach is tested against a particular pathogen, the design priorities will obvisouly consist of a high affinity along with good selectivity to specifically block the lectin adhesion on the host tissues. To do so, the design is likely to be strongly influenced by the natural ligand of the lectin in terms of valency, topology, and density of carbohydrates. On the other hand, the study of processes involving lectins sometimes requires tools that can perturb the normal association of a lectin with its natural ligand. The signaling processes often associated with receptor clustering, the selectins-mediated adhesion, and rolling in inflammatory responses and the cis−trans competition occurring within glycoprotein−cell surface lectin lattices are examples of processes that might require the design of specific tools able to impact the natural interaction to modulate the biological response. For each situation, either monovalent glycomimetic or multivalent glycosylated structure approaches have advantages, specific features, and benefits. Choosing between the two strategies usually necessitates a clear understanding of the phenomenon under study. Synthetic glycoconjugates generally would not reproduce exactly the valency and topology of the natural ligands. Nevertheless, the binding properties obtained in most cases are in line with possible applications in vivo and as therapeutics. When designing a multivalent ligand, the most widely adopted approach starts from the multivalent lectin structure and attempts to build a multiglycosylated structure that would best fit the lectin topology (lectin-based design). The intensive investigations in this direction using a combination of organic synthesis, drug design, and biological evaluations in vitro, in vivo, and sometimes in animal models are now being increasingly reported. A ligand-based design that could prove very efficient in the future would be to start from the natural ligand and to design a simplified and optimized structure (Figure 9). This approach is however tremendously complicated by the difficulty to gain insight into the natural valency, topology, and density of carbohydrates’ presentation. Fortunately, both approaches require similar synthetic concepts. Chemists and biochemists have designed a large series of multivalent glycoconjugates displaying various valencies and topological properties (Figure 10). Glycoclusters display a limited but synthetically controlled number of binding epitopes. Glycodendrimers include an additional branching point in the structure leading to higher valencies and ball-shaped volumes while controlling valency and conserving a single molecule property important for drug regulators. Glycopolymers can reach higher valencies with less control, although polymerization

Figure 9. Mimicking of natural ligand presentations in their physiological context.

Figure 10. Different types of multivalent glycoconjugates.

techniques now allow for a tight control of the oligomers valency.93 The increase in valency usually provides better ligands, while the toxicity of the polymer backbone needs to be addressed and size distribution can represent a serious drawback for approval of such potential drugs. Glyconanoparticles can also provide larger valencies (typically 50−150 residues) with various populations at the surface of the nanoparticle. Such nanomaterials have recently witnessed a rapid development toward biological applications, and recent reports in vivo and in animal models against pathogen infections are very encouraging.94,95 Conjugation of carbohydrate epitopes to specific positions of proteins is a rather challenging endeavor, and some reports in this field provided interesting data for the design of antiinfectious drugs.96−98 Again, the nature of the carrier protein is sensitive with a tight control over toxicity and valency for optimal biomedical applications. 2.4. Analytical Techniques

The characterization of lectin interactions with either a small molecule (glycomimetic) or a glycosylated multivalent ligand is of crucial importance when studying the lectins’ roles in F

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Figure 11. HIA determination of minimum inhibitory concentrations (MIC) using red blood cells. (A) Determination of minimal lectin concentration required for hemagglutination; (B) inhibition of hemagglutination using increasing concentrations of ligand.

biological context or when developing therapeutic approaches blocking these interactions. The determination of the dissociation constant KD in vitro is of crucial importance. However, its measurement can be quite challenging and does not always reflect the potency of the synthetic candidates in the inhibition of a specific process in vivo. Therefore, inhibitory potency measurements (IC50) can be measured using several techniques (e.g., competition experiments) and can be highly informative. Importantly, assays using competing molecules or surfaces and IC50 determination in general are highly dependent on the experimental conditions, and comparison of results is only meaningful when ligands are tested within the same assay.91 The biochemical techniques used in the characterization of carbohydrate−lectin interactions have been recently reviewed.99,100 Therefore, we intend to briefly describe herein the different approaches and the information that can be extracted from different experimental setups either with glycomimetics or with multivalent architectures. To appropriately interpret the results of such experiments, it is an absolute necessity to understand the specifics of the experimental design that could lead to a misleading overinterpretation. 2.4.1. Determination of Inhibitory Potency (HIA, ELLA, SPR). Inhibitory potency depicts the ability of a ligand to inhibit a specific lectin-mediated process in a particular experimental setup. Most assays are usually normalized with respect to a monovalent standard ligand of this lectin, and meaningful results are reported as relative inhibitory potency. They are typically measured through competition assays where the monovalent or multivalent synthetic ligand is competing with glycosylated surfaces such as red blood cells (HIA), glycosylated polyacrylamide adsorbed in polyester 96-wells plates (ELLA), or functionalized dextran adsorbed on gold surfaces (SPR). These types of competition assays are useful quantitative tools especially because the actual mechanism of interaction is generally either unknown for multivalent interaction or the result of multiple competing processes. Therefore, competition assays provide an overall informative relative potency. Hemagglutination inhibition assays (HIA) are usually performed using rabbit or guinea pig blood cells, and a simple naked eye visual observation of the wells (Figure 11) allows for the determination first of the minimum lectin concentration needed for hemaglutination, and then of the minimum inhibitory concentrations for a given ligand (MIC). The MIC represents the minimum ligand concentration that prevents the lectinmediated aggregation of erythrocytes. The comparison of several HIA assays between different reports is not possible because the quality and origin of the blood samples can cause fluctuations in the results obtained. This approach provides a rapid and low-cost screening of ligands and can be considered as an initial filter for

further studies. Some compounds would cause hemolysis of the erythrocytes during the assays. The quantity of ligands and lectins required in such assays is rather high (in the high micromolar range), and therefore sometimes restrictive for highly valuable ligands obtained in limited amounts after long synthetic steps. Enzyme-linked lectin assay (ELLA) appears as a common tool for the evaluation of binding properties of monovalent and multivalent lectin ligands (Figure 12). To mimic the cell surface, a glycosylated polymer (i.e., polyacrylamide) is coated on the bottom of a microtiter plate, and the adhesion of a biotinylated lectin is evaluated. A library of soluble compounds can be tested for their ability to inhibit the binding. This technique still requires rather sensible quantities of ligands and lectins even though the UV−vis detection used here is rather sensitive. The quantitative data obtained with ELLA are reliable, but, again, inter-reports comparison is not trivial due to the differences in experimental setups between research groups (e.g., lectin and/or ligand concentration, HRP system used for visualization). ELLA experiments are also sensitive to aggregation of lectins in the presence of multivalent ligands. Synthetic multivalent ligands displaying a strong ability to aggregate lectins can actually promote the adhesion of lectins onto the surface through the establishment of a cross-linked network, thus yielding biased results and “negative inhibitions”. Surface plasmon resonance (SPR) is a powerful bioanalytical technique that allows the real-time monitoring of adhesion onto a modified surface, hence becoming a major technique in the study of receptor−ligand interactions (Figure 13). Application to multivalent lectin−glycoconjugate interactions is quite straightforward in terms of experimental setup, but the experiemental design and data processing requires a strong knowledge of the mechanism of interaction. Indeed, in the direct approach (immobilized lectin and ligand in the flow), the observation of the multivalent ligand association and dissociation from the surface provides that sensorgrams need to be fitted using kinetic models to obtain kinetic (kon and koff) and thermodynamic parameters (Kd). However, the choice of the fitting model necessitates rigorous knowledge of the mechanism of interaction. Fortunately, SPR instruments can also be used in competition experimental setups in which the synthetic multivalent ligand competes with a glycosylated surfaces (Figure 13). The titration curves provide a reliable and easy access to IC50 values. As for other competition techniques, comparison between different reports is inaccurate because the nature of the buffer, flow, concentrations of bioanalytes, and also the type of the sensorchips can strongly influence the outcome of the study. Dynamic light scattering (DLS) provides access to the size of aggregates formed in solution upon interaction of multivalent G

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neous samples. This technique therefore requires great precautions in the experimental design and in the validation of results. However, DLS remains a very efficient way to determine if the interaction with a given multivalent ligand generates large aggregates. Carbohydrate microarrays also demonstrated to have powerful applications for the determination and study of multivalent lectin−carbohydrate interactions.101,102 A rapid screening of ligands is possible with minute amounts of material as low as a few picomoles. Relative quantification of these interactions is also possible and provides IC50 as well as Kd values.103 Finally, fluorescence-polarization experiments are based on the fact that a fluorescent molecule undergoes less depolarization when bound to a receptor than when unbound. This approach can be used for screening a library of competitors against the binding of fluorescein-labeled saccharides toward an appropriate lectin. This strategy has been applied to several lectins for the rapid identification of potential high affinity ligands.104−106 2.4.2. Determination of Thermodynamics Parameters (ITC). Isothermal titration microcalorimetry (ITC) is probably the most powerful technique providing in a single experiment all thermodynamic parameters (ΔG, ΔS, ΔH, Kd) but also the stoichiometry of the complex (n). The bioanalytes (glycoconjugates and lectins) are in solution (Figure 14) and do not necessitate labeling or grafting to a surface, and the data are therefore not influenced by an external factor. Titration can be performed in two opposite setups with either the lectin added dropwise into a solution of ligand or vice versa. Both systems provide useful data and allow a reliable determination of the thermodynamics and stoichiometry of the multivalent interaction studied. However, ITC requires a large amount of material, and it could be highly sensitive to aggregation when working with multivalent glycoconjugates. 2.4.3. Determination of Structural Features (X-ray, AFM, NMR). X-ray crystallography is commonly applied to the study of lectin−carbohydrate interactions. For monovalent ligands, cocrystallization or soaking has enabled researchers to solve numerous structures that are always highly informative in understanding the interaction and in further optimizing or designing glycomimetics. Crystallization attempts of complexes between multivalent glycoconjugates and lectins have been significantly less successful. First, the size and flexibility of glycoconjugates are often detrimental for their insertion within the crystal lattice, thus preventing crystal growth. Also, when stable crystals are obtained and diffraction

Figure 12. ELLA determination of inhibitory concentrations (IC50) in competition with glycopolymers adsorbed on surfaces.

ligands with lectins. The experimental setup of this technique is rather difficult to control because aggregation is most likely a kinetically controlled process that frequently yields heteroge-

Figure 13. Schematic representation of a surface plasmon resonance (SPR) competition assay for the determination of inhibitory concentrations (IC50) in competition with biotinylated glycopolymers adsorbed on streptavidin-grafted surfaces. H

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Figure 14. (Left) Schematic representation of a calorimeter with titration of ligands into a solution of lectins. (Middle) Typical thermogram obtained. (Right) Thermodynamic parameters obtained from the titration curve.

Figure 15. Schematic representation of Siglec-1−11.

3. SMALL MOLECULES AS HIGH AFFINITY LIGANDS OF LECTINS

data can be collected, only the interacting part of the glycoconjugate (typically the carbohydrates within the binding

3.1. Modified Sialosides and Interactions with Myelin Associated Glycoprotein (MAG)

sites) is well-resolved while the connecting linker arms and the core scaffold are too flexible and have to be modeled. When glycoconjugates and lectins interact through aggregative

Myelin Associated Glycoprotein (MAG or Siglec-4a) belongs to the sialic-acid-binding immunoglobulin-like lectin (Siglec) superfamily, a group of at least 16 membrane proteins that bind to sialylated glycoconjugates.111 MAG contains five immunoglobulin-like repeats and is specific for α-(2,3) linked N-acetylneuraminic acid. It is present on myelin membrane and involved in axon-myelin stability. MAG is a therapeutic target because it also inhibits the regeneration of axons after injury.112 Inhibition is mediated by the binding of MAG to sialylated brain gangliosides,113 and competing with this interaction is therefore a challenge for brain injury treatment.114−117 The crystallographic data for MAG bound to its sialylated ligand are not yet available. Siglecs are composed of N-terminal V-type immunoglobulin-like (Ig) domains (Figure 15) also referred to as the carbohydrate recognition domain (CRD) along with several Ig-like domains with a single transmembranar domain that is connected to the Cterminal tail usually bearing a cytoplasmic tyrosine motif such as the immunoreceptor tyrosine-based inhibitory motif (ITIM). The minimum MAG binding epitope was identified as the tetrasaccharide Neu5Acα(2,3)Galβ(1,3)[Neu5Acα(2,6)]GalNAc (Figure 16) from the glycosphingolipid

mechanisms, atomic force microscopy (AFM) provides insights regarding macromolecular arrangements of the ligands and lectins.72,73 Nuclear magnetic resonance (NMR) can also be applied for the studies of monovalent and multivalent carbohydrate−lectin interactions.107 A series of recent reports have applied this technique using saturation-transfer difference (STD) in solutions of lectin and multivalent ligands107−110 but also using cells.109 The NMR mapping of a lectin can be also applied to the determination of the specific amino-acid residues of a lectin interacting with a ligand in solution. An accurate threedimensional description of the complex can therefore be obtained from these data as a substitute to crystallographic studies. I

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Figure 16. Structure of glycosphingolipid GQ1bα with the tetrasaccharide Neu5Acα(2,3)Galβ(1,3)[Neu5Acα(2,6)]GalNAc in red.

Table 1. Modified Sialosides and Interactions with Myelin Associated Glycoprotein (MAG)

GQ1bα.113,118,119 Structure−activity relationship studies120,121 have highlighted the role of the Galβ(1,3)GalNAc core as a spacer positioning the two sialic acid residues in appropriate spatial orientation for proper binding to MAG.118,122 Nevertheless, this disaccharide was later demonstrated to contribute to binding through hydrophobic interactions using trNOE123 and STD124 NMR techniques. Given the high similarity among siglecs, the design of MAG inhibitors can also find applications against CD22 (Siglec-2), for instance.125 This demonstrates that even if a careful molecular design for a specific target is moderately or poorly successful, it can also be applied to other similar targets with more success. The design of MAG inhibitors has been mostly based on chemical modifications of the sialic acid scaffold either as a monosaccharide or as an oligosaccharide moiety. The first study focused on the acylation motif at the NHAc group121 providing improved binding properties (Table 1, entry 1). In a parallel study, a synthetic pentasaccharide could also be identified as an improved ligand of MAG (Table 1, entry 2) incorporating an AllNAc residue, which proved beneficial in comparison to the natural GlcNAc moiety.122 Later, the Galβ(1,3)GalNAc core disaccharide was replaced by a hydrophobic disialylated biphenyl

residue (Table 1, entry 3), which simplified greatly the molecular structure and provided affinities similar to those of MAG along with good pharmacokinetic properties.126 A further simplification allowed the introduction of a single sialic acid residue (Table 1, entry 4) while preserving potent inhibition of MAG.127 The introduction of an amide group at the 9-position of sialic acid (Table 1, entries 5,6) provided potent MAG ligands,128−130 while a carbasugar analogue was detrimental.131 The first submicromolar MAG inhibitor was obtained using a modified Galβ(1,3)GalNAc core (Table 1, entry 7) bearing a biphenyl substituent at the 6-position.132 The identification of a secondary binding site (subsite association, Figure 5c) by NMR techniques afforded another submicromolar MAG antagonist (Table 1, Entry 8) using a sialic acid scaffold.133 3.2. Modified Fucosides and Glycoclusters and Interactions with Pseudomonas aeruginosa Lectin B (LecB or PA-IIL)

Pseudomonas aeruginosa is an opportunistic pathogen involved in a large number of diseases134 such as septicemia and urinary tract infections but also lung infections in immuno-compromised and cystic fibrosis (CF) patients.135,136 This bacterium utilizes oligosaccharide recognition for anchoring to the host cells with a collection of carbohydrate binding proteins including soluble J

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Figure 17. (Left) Graphical representation of tetramer of LecB from P. aeruginosa in complex with L-fucose (PDB code 1GZT).146 (Right) Close view of the fucose binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, calcium ions by spheres, and hydrogen bonds by dashed lines.

lectins and adhesins exposed on pili, flagella, or fimbriae.137−140 LecA (PA-IL) and LecB (PA-IIL) have been identified as two soluble lectins in P. aeruginosa, specific to galactosides and fucosides, respectively.141−143 LecA binds to α-galactosyl residues present on glycosphingolipids in lung epithelial cell membranes,144,145 while LecB binds to several fucosylated or mannosylated epitopes but display higher affinity for the Lewisa oligosaccharides.146,147 Monosaccharides (i.e., fucose, mannose, and galactose) have been tested to limit bacterial infection through competition with LecA and LecB.148 Both galactose and fucose were active against the spread of infection in a murine pneumonia model149 and particularly in combination with antibiotics.150 Adhesion of P. aeruginosa to human respiratory epithelial cells was also significantly prevented by human milk oligosaccharides.151 Plant and microbial polysaccharides were identified as LecA and LecB ligands with potential applications in gastrointestinal and external infections.152 The design of high affinity ligands of LecA and LecB can therefore provide an efficient antiadhesive strategy153 against P. aeruginosa infection. Given the increasing antibiotic resistance154−156 observed for some isolates of P. aeruginosa, such antibacterial strategy can be highly valuable. Because of the very unique involvement of two calcium ions in the carbohydrate binding site (Figure 17), LecB displays unusual high affinity toward fucose. 146 It also binds to other monosaccharides presenting hydroxyl groups in orientation suitable for coordination of the two calcium such as L-galactose, 143,157 D-mannose, and D-arabinose, albeit with lower affinity. a Highest affinity is obtained for Lewis oligosaccharides, which is proposed to be its natural ligand on host tissue.147 The mannose scaffold can be used for the design of LecB ligands as exemplified very recently by a series of modifications at the 6-position of methyl α-D-mannopyranoside.104 The best ligand identified displayed a hydrophobic sulfonamide (Table 2, entry 9) using a competitive fluorescence assay for the first time for this lectin although previously reported for galectins106 and FimH.105 The crystal structure of the sulfonamide in the binding site of LecB highlighted a hydrogen bond between the sulfonamide and the protein as well as hydrophobic contacts with the aromatic moiety.104 A similar approach toward the modification of the Lewisa trisaccharide identified a N-fucosyl amide158 as a potent LecB ligand (Table 2, entry 10), while a divalent N-fucosyl amide (Table 2, entry 11) displayed similar

binding properties. The design of Fucα(1,4)GlcNAc disaccharides as analogues of Lewisa trisaccharide yielded another potent ligand159 (Table 2, entry 12). Crystallographic studies identified contacts between the GlcNAc residue and the lectin, while the triazole moiety was pointing toward the solvent.159 The affinity was moderately improved when this molecular scaffold was conjugated on a divalent oligoethylene glycol moiety160 (Table 2, entry 13). A series of multivalent glycoclusters were studied and displayed high affinities toward LecB with some of them applied in studying biofilm dispersion. Oligonucleotides were used as core scaffolds for the syntheses of glycoclusters.102,161,162 Pentaerythritol was desymmetrized and used as a core scaffold yielding a potent decavalent LecB ligand163 (Table 2, entry 14). The valency increased the affinity for the lectin but with a plateau for 4−6 fucosyl residues. Therefore, the tetravalent glycocluster (Table 2, entry 15) was investigated further with a 15-mer oligonucleotide tag used for quantitative binding assays103 on carbohydrate microarrays164,165 and displayed a good improvement in comparison to fucose.166 In the same study, a central mannose phosphodiester core (Table 2, entry 16) was also reported as a valuable scaffold for the design of high affinity LecB ligands.166 Oligopeptides have been used for the design of multivalent lectin ligands,167,168 and the screening of a combinatorial library of 390 625 members provided a glycopeptide dendrimer as a potent LecB ligand (Table 2, entry 17).169 The C-fucoside used for the conjugation was also grafted to a tetravalent glycopeptide containing D-amino acids170 (Table 2, entry 18) elongating the distance between the carbohydrate epitope and the core peptide, thus improving the binding properties toward LecB. Increasing the valency to eight C-fucosyl residues (Table 2, entry 19) yielded a 440-fold improvement versus fucose as measured by ELLA.171 Introduction of an aromatic residue at the anomeric position of fucose and conjugation with oligopeptides in two combinatorial libraries of 15 625 members identified a tetravalent glycopeptide dendrimer (Table 2, entry 20) not only as a potent ligand of LecB but also with inhibitory and dispersion properties against P. aeruginosa biofilm.172 This is one of the very few reports on the activity of such glycoclusters as antibiofilm agents along with a calix[4]arene-based glycocluster.173 A cyclic oligopeptide was used for the synthesis of a hexadecavalent glycocluster (Table 2, K

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Table 2. Mono- and Multivalent LecB Ligands and Their Binding Properties

L

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Figure 18. (Left) Dimer of hGal-1 complexed with N-acetyllactosamine (PDB code 1W6PO).177 (Right) Close view of the oligosaccharide binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, and hydrogen bonds by dashed lines.

from these data for each portion of the disaccharide, therefore identifying the 3′-position of Lac/LacNAc (subsite A) as crucial for the design of such inhibitors. The inhibition of galectins by small molecules has been investigated190−192 and provided a large set of data for the structure−activity relationship of Gal-1 and -3. The binding properties summarized below (Table 3) will only comment on the inhibitory properties reported toward galectins Gal-1 and -3 for clarity. The multivalent ligands of galectins have been reviewed elsewhere192 and will not be discussed herein. Derivatization at the 3′-position of Lac or LacNAc was one of the earliest strategies investigated. A structure−activity relationship study of a 12-compound library identified the 2,3,5,6tetrafluoro-6-methoxy-benzamido group (Table 3, entry 22) as a potent Gal-3 ligand, which is about 50 times more potent than the corresponding N-acetyllactosaminide.193 Later, the continuation of this work gave access to the high-resolution X-ray crystallography data for this compound bound in the CRD of Gal-3.194 The affinity enhancement could be attributed to the stacking of Arg144 side chain with the aromatic benzamido moiety of the inhibitor leading to the entropically favorable displacement of a water molecule. A second generation of ligands was therefore investigated, thus identifying a 3-carboxy-2naphthamido group as another pharmacophore (Table 3, entry 23).194 The 3′-position of LacNAc was also functionalized with a thioureido aromatic moiety195 providing moderate inhibitory properties toward both Gal-1 and Gal-3 (Table 3, entry 24). The simultaneous introduction of three modifications on a galactoside scaffold such as a sulfate at the 2-position, a benzamido group at the 3-position, and a sulfur exo-anomeric position led to methyl β-D-galactosides (Table 3, entry 25) with moderate affinities for Gal-1 and -3.196,197 The aromatic substituent at the 3-position shifted the Arg144 residue from its original position and moved it in close vicinity to the 2-position. Introduction of the sulfate anion generated an electrostatic beneficial interaction with the protein. Both substituents at the 2- and 3-positions therefore act as “tweezers” for the arginine residue. 3-(1,2,3Triazolyl)-β-D-thiogalactosides have also been reported (Table 3, entry 26) and provided inhibitors with micromolar Kd values.198 Another strategy used alkylation at the 3-position of galactose199,200 (Table 3, entries 27,28) or 3′-position of LacNAc201 (Table 3, entry 29) with hydrophobic benzyl ethers leading to moderate to strong enhancement of affinities toward both Gal-1 and -3. Nevertheless, the LacNAc scaffold with an

entry 21), and the best affinity was measured by both ELLA and ITC for this macromolecule.174 3.3. Modified Galactosides and LacNAc Derivatives and Their Interactions with Galectins

Galectins are a family of ubiquitous lectins, present in vertebrates, invertebrates, and fungi.175 They are located on the cell-surface, interacting with glycolipids or glycoproteins, but also inside the cells, interacting with cytoplasmic or nuclear proteins. Galectins play an important role in many biological functions and have been shown to be involved in inflammation and tumor development.176 Galectins are classified in different families based on their architecture, but they always contain globular galectin-type CRDs with specificity directed toward β-galactosides (Figure 18). Several galectins have been identified as targets for the development of therapeutic agents due to their role in various pathological disorders, and the present view will particularly focus on Gal-1 and -3. Gal-1178,179 is implicated in cell survival and proliferation180 as well as regulation of immune response, allergies, inflammation, metastasis, or even host−pathogen interactions.181 Gal-3 is probably the most intensively investigated lectin182−184 due to its role in metastasis,184 cancer apoptosis,183,185 breast cancer,186 or cancer resistance.187 Gal-1 and -3 are also of special interest as targets in liver malignancy.188 The crystallographic structure of Gal-3 CRD in complex with lactose and LacNAc189 (Figure 19) indicates interactions mainly through the Gal residue, while the GlcNAc motif displays fewer interactions. Four subsites (A, B, C, and D) have been identified

Figure 19. Representation of the subsites for the design of galectins ligands. M

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Table 3. Ligands of Gal-1 and Gal-3 and Their Binding Properties

N

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Table 3. continued

approach.214 1-Thio-β-D-galactopyranosides represent another possible scaffold for the design of galectins ligands with a large aromatic aglycon identified initially as a moderate Gal-1 and -3 inhibitor215 (Table 3, entry 43). 2-Naphthyl 1-sulfonyl-β-Dlactopyranoside (Table 3, entry 44) highlighted the preference for a sulfone exo-anomeric group.216,217 A series of C-galactosides were tested against Gal-1 and -3 inhibition,218 and a conjugated aromatic aglycon (Table 3, entry 45) was preferred, and while moderate inhibitions were measured by HIA experiments, good selectivity toward Gal-1 versus Gal-3 was obtained.

additional hydrophobic phthalimido substituent at the 2position201 provided the best results not only in terms of affinity but also in terms of selectivity between Gal-1 and -3 (more than 230 in favor of Gal-3), which is another challenge in such drug design approaches. Modifications at the 2-position of LacNAc202 (Table 3, entry 30) or Lac203 (Table 3, entry 31) also provided inhibitors of Gal-1 and -3. The design of C2-symmetrical thiodigalactosides provided a series of highly potent inhibitors of galectins using again derivatization at the 3-position of the galactose moieties to tune the binding properties toward the lectin. Ester modifications at the 3-position of such thiodigalactosides activated apoptosis in papillary thyroid cancer,204 but also provided antimigratory effects in cultured lung and prostate cancer cell lines.205 While the ester bond can be readily hydrolyzed in vivo, the incorporation of amido moieties at the 3-position proved also beneficial, and several substituted benzamides are promising candidates for potential anticancer applications205−207 (Table 3, entries 32−34). The affinity for Gal-1 and -3 could be further improved using triazoles at the 3-position201,208 (Table 3, entries 35,36), and such inhibitors displayed Kd values in the low nanomolar range, being the most potent ligands of these lectins. Although the affinities were increased for the triazolyl-based ligands, the selectivity between Gal-1 and Gal-3 was not particularly high201 (Table 3, entry 36), while the amide-based ligands proved very selective toward Gal-3 versus Gal-1 (Table 3, entry 33).206 More recently, the C2-symmetrical thioditaloside209 (i.e., the C2-epimer of thiodigalactosides) scaffold was investigated and demonstrated as another inhibitor scaffold of Gal-3 (Table 3, entry 37), thus providing access to potentially more selective galectins inhibitors. The corresponding talosides were also evaluated as monosaccharide scaffolds and displayed moderate inhibitory properties with a 3-amido group210 (Table 3, entry 38), and the introduction of a sulfate at the 2-position along with a hydrophobic ester at the 3-position proved more beneficial211 (Table 3, entry 39) not only in terms of affinities but also for a better selectivity toward Gal-3. Similarly, the mannose scaffold was studied (Table 3, entry 40) and provided a moderate Kd value in the millimolar range against Gal-3 but a good selectivity for this lectin versus Gal-1.212 A library of 50 aldoximes derived from O-β-D-galactopyranosyl hydroxylamine and aldehydes was evaluated as Gal-3 inhibitors.213 The most potent member of this library comprised a 3indolyl residue (Table 3, entry 41). Further improvement was obtained by introducing a second binding motif at the 3-position of galactose (Table 3, entry 42) in a fragment-based design

3.4. Application to the Cholera Toxin AB5 System

The AB5 toxins are virulence factors involved in whooping cough caused by Bordetella pertussis and in major food or water-borne diseases caused by bacteria such as Vibrio cholera, Shigella dysenteria, and enterotoxigenic strains of E. coli.219 The AB5 toxins consist of a B-subunit pentamer binding to specific glycoconjugates on host cells and a catalytic A-subunit with different type of cell toxicity depending on bacteria.220 Cholera causes epidemics mostly in India and Africa regions but also in Haiti, and the 2010 outbreak resulted in 300 000 cases worldwide with more than 7500 deaths.221 In the cholera toxin (Ctx), the pentameric lectin B-subunit (CTB) specifically binds to the oligosaccharide moiety of ganglioside GM1 (Figure 20).222−226 Because of the extensive network of hydrogen bonds established between the amino acids and sugar residues, subnanomolar affinity is observed for the interaction between CTB and the pentasaccharide.227,228 In depth microcalorimetry (ITC) studies of the GM1−CTB multivalent interactions concluded that the high affinity observed was predominantly due to the conformational preorganization of the pentasaccharide rather than through cooperativity.228 Design of multivalent and monovalent ligands of CTB is therefore of great importance for the discovery of anti-infective agents.230−233 While multivalent scaffolds have been recently reviewed234 as nanomolar235 and up to picomolar236 bacterial toxin inhibitors, the present section will focus on monovalent approaches for the inhibition of cholera toxin (CTB) using rational drug design and medicinal chemistry strategies. CTB and the B-subunit of the heat-labile enterotoxin (LTB) have 80% sequence homology, and their binding sites are highly comparable to similar modes of action in vivo.233 The data for these glycomimetics will therefore be discussed against either CTB or LTB. Aglycon modification is a common approach for the improvement of binding properties toward lectins because hydrophobic interactions are usually possible in the vicinity of O

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the pure α-anomer could then be achieved in the same study, and Kd values in the micromolar range could be measured by pulsed ultrafiltration,240 and these values were in agreement with ITC experiments. Further design with a longer aglycon incorporating a piperazine motif (Table 4, entry 48) provided another CTB ligand.241 Dimerization could be readily achieved through conjugation of the amine group with various difunctional spacers yielding low micromolar ligands, which could then be cocrystallized with the CTB pentamer. The piperazine being identified as a positive modification, the m-nitro position was then investigated for the design of improved CTB ligands. A 1:1 mixture of anomeric epimers with four different amide substituents provided a thiophenyl derivative (Table 4, entry 49) with IC50 values (ELLA) in the high micromolar range toward CTB with solid-state studies.242 Yet reaching submicromolar binding or IC50 with monovalent ligands has proven to be a rather complicated task. The preorganization of a ligand with another protein such as serum amyloid P (SAP), a strategy also used for the design of Shiga toxin ligands (see section 4.1), and the introduction of a proline group (as a recognition motif for SAP) on the aglycon derivative (Table 4, entry 50) provided CTB ligand with an IC50 in the high micromolar range without the preorganizing SAP but submicromolar IC50 when noncovalently bound to SAP.243 The GM1 pentasaccharide utilizes the galactose and sialic acid terminal residues as principal binding epitopes toward CTB. The design of C-glycosides incorporating both monosaccharides was investigated to provide nonhydrolyzable ganglioside mimics. A small library of compounds was synthesized, and a submillimolar ligand (Table 4, entry 51) was identified as a lead candidate for the design of multivalent glycoconjugates.244 Weak affinity chromatography measurements were slightly sensitive to pH, and relative potency (β) against m-nitrophenyl α-D-galactopyranoside was rather poor. The AB5 toxin assembly forms a ring with a central pore at the C-terminus of the A-subunit. Evaluation of small molecules as ligands of this particular binding site led to the discovery of a noncarbohydrate inhibitor of the AB5 toxin. 3-(Methylthio)-1,4diphenyl-1H-1,2,4-triazolium bromide (MDT) was cocrystallized with LTB (Table 4, entry 52) and was indeed blocking the pore.245 No binding constant could be reported because MDT is therefore a lead compound for the design of Ctx antagonists targeting the assembly of the AB5 system rather than the more traditional CTB-host interaction. More recently, the synthesis of a large family of noncarbohydrate CTB ligands was reported, and the best ligand (Table 4, entry 53) displayed high micromolar affinity, and STD NMR studies provided valuable structure− activity relationship information for the further design of improved CTB ligands.246

Figure 20. (Top and middle) Two orthogonal views of B-subunit pentamer from cholera toxin (CTB) associated with the GM1 pentasaccharide (PDB code 3CHB).229 (Bottom) Close view of the oligosaccharide binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, and hydrogen bonds by dashed lines.

3.5. Application to FimH (E. coli)

the lectin’s binding site. Screening of 35 galactosides against CTB selected the m-nitrophenyl α-D-galactopyranoside (Table 4, entry 46) displaying a submillimolar IC50 value,237 which represents a relative potency (β) of 60 in comparison to galactose as the minimal epitope for CTB. The same mnitrophenyl α-D-galactopyranoside displayed improved binding toward LTB,238 and the screening of 15 structural modifications on the aromatic aglycon moiety revealed similar binding features for each glycomimetic with a poor preference for the morpholine substituent (Table 4, entry 47) using a 1:1 mixture of anomers.239 This morpholino-substituted galactoside could be cocrystallized in the binding site of CTB with eight conformations observed in the solid state. The preparation of

The fimbrial adhesin FimH is a protein located on the tip of type 1 pili (or fimbriae) from uropathogenic E. coli.247 Its external domain is a mannose-binding lectin that binds to glycosylated uroplakin receptors on the uroepithelium, therefore participating in the establishment of urinary tract infections.248 Structural studies defined the hydrogen-bond network necessary for mannose specificity.249 The design of carbohydrate-based inhibitors of type 1 fimbriae-mediated bacterial adhesion has attracted a lot of interest in the past decades.250 Multivalent glycoconjugates251 as well as monosaccharide ligands of the lectin have been intensively studied and will be presented separately herein. Applications as potential antiadhesive drugs P

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Table 4. Monovalent Ligands of Cholera Toxin B (CTB)

against bacterial infection153 are becoming important due to the increasing antibiotic resistance of E. coli strains.252 FimH is an interesting model for such studies because its affinity for mannosides is independent of E. coli pathotypes.253 FimH affinity for mannose is modest, but a 100-fold increase is observed when binding to glycans exposing terminal Manα(1,3)Manβ(1,4)GlcNAc trisaccharide253,254 or oligomannosides.255 Independently, the addition of alkyl chains at the anomeric position of a mannose residue in α-configuration resulted in high affinity ligands (Table 5, entry 54).256 The stabilizing effect of the aryl chain is due to hydrophobic interaction with the so-called “tyrosine gate”249,256,257 formed by two tyrosine (Tyr48 and Tyr137) residues at the entrance of the binding site (Figure 21). The “tyrosine gate” was investigated further, and the Tyr48 residue was mutated to demonstrate its limited influence on the protein recognition of heptyl α-Dmannopyranoside.258

Given the importance of a hydrophobic residue as aglycon for optimal binding properties to FimH, the 4-methylumbelliferyl α259 D-mannopyranoside (Table 5, entry 55) and p-nitrophenyl α260 D-mannopyranoside (Table 5, entry 56) were early identified as improved ligands for the bacterial lectin. Derivatization at the nitro moiety through a squaramide moiety provided high potency ligands for FimH (Table 5, entries 57−59) using three different types of inhibition assays along with the identification of an o-chloro substituent on the phenyl aglycon.261−263 The mode of inhibition of such squaramides could occur through either specific interaction at the lectin’s binding site or unspecific bioconjugation through a covalent bond created by the displacement of the ethoxy group (OEt) of the squaramide by an amine moiety from the lectin’s binding site. The covalent mode of inhibition of such ligands has recently been questioned in another study,264 suggesting an inhibition potency that remains rather independent of the putative cross-linking reaction (Table 5, entries 60). Optimization of the binding properties toward FimH was continued using biaryl aglycons in a structure−activity relationship study to identify the best substituent around the large aromatic anomeric moiety. The 3,5-diester substitution pattern displayed an affinity improved by a 100-fold in comparison to the reference heptyl α-D-mannopyranoside (Table 5, entry 60).105 A divalent compound was also investigated and provided similar binding properties. The next developments focused on the design of orally active FimH inhibitors.265,266 For that purpose, a set of structural modifications of the aglycon were designed to improve solubility267 but also pharmacokinetics,268,269 selectivity,269 and in vivo properties.265 The introduction of an o-chloro substituent on the phenyl ring provided another hit compound in the series (Table 5, entry 61), and the importance of this chlorine atom can be compared to the squaramide situation (Table 5, entries 57−59). The o-chlorine substituent could also be replaced with an o-methoxy group (Table 5, entry 62) and

Figure 21. (Left) Graphical representation of the lectin domain of the FimH adhesion from E. coli in complex with butyl α-mannopyranoside (PDB code 1UWF).256 (Right) Close view of the mannose binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, and hydrogen bonds by dashed lines. Q

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Table 5. Monovalent Ligands of FimH

provided similar inhibition properties.270 Changing the ester moieties to amides increased further the inhibition toward FimH-mediated hemagglutination, and the concomitant introduction of a o-trifluoromethyl group (Table 5, entry 63) provided one of the best FimH ligands to date271 identified as a lead compound. The prevention of biofilm formation with this compound (Table 5, entry 63) was inhibited with an IC50 value of 43 nM.271 Although the inhibitory properties of the monoamide derivative266 (Table 5, entry 64) were slightly decreased in comparison to the 3,5-diamide (Table 5, entry 63), its in vivo applications were improved, and this compound appears now as a candidate for preclinical studies.272 Finally, introduction of one phenyl group in the aglycon by an indoline residue (Table 5,

entry 65) provided another lead compound with in vivo studies reported in mice.273 Triazolyl-based aglycons were also evaluated as pharmacophores,274 and the best ligand (Table 5, entry 66) displayed inhibitory potency similar to that of heptyl α-Dmannopyranoside. Because E. coli infections were also shown to be involved in certain forms of Crohn’s disease,275,276 an antiadhesive strategy was applied through a family of 11 mannosylated heterocycles tested ex vivo against this FimH-mediated bacterial infection.277 A large aromatic aglycon composed of two thiazoles and one pyrazine moieties provided the best hemagglutination inhibitory properties (Table 5, entry 67). R

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Table 6. Multivalent Ligands of FimH

S

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Table 6. continued

FimH,282,283 and the importance of the core moiety was demonstrated (Table 6, entries 71,72). The importance of the inhibition assays was also relevant because two ELISA assays performed by the same group provided different IC 50 values.282,284 More recently, the conjugation of a trivalent mannosylated dendron based on tris(hydroxymethyl)aminomethane with a nanoscale diamond was successfully achieved.285 The inhibitory properties of such innovative glycocluster were determined using a modified ELISA assay due to the high aggregative properties of such ligands. These glycoclusters induced high aggregation of FimH in solution, and removal of the bacteria could be performed using a simple 10 μm pore-size filter demonstrating the possible applications of such glyconanomaterials for decontamination. Pentaerythritol is a common tetravalent molecular scaffold used for the design of glycoclusters. The tetra-azido derivative conjugated through azide−alkyne 1,3-dipolar cycloaddition with various alkynylated mannosides (Table 6, entry 73) provided a high affinity ligand of FimH.286 Nevertheless, further developments in this direction were not reported, probably due to the

The second approach for the design of FimH high affinity ligands is through the use of multivalency to take advantage of the “cluster effect”. The synthetic strategy for the preparation of such glycoclusters used a central multifunctional scaffold and a prefunctionalized mannoside. The following examples are classified on the basis of their central scaffold. One of the earliest examples of multivalent ligand for FimH is a tetravalent glycocluster based on azamacrocycles279 using a thiourea conjugation strategy (Table 6, entry 68). This initial molecular design provided a very potent FimH ligand, but the increase in valency to the hexavalent thiourea-based glycocluster280 (Table 6, entry 69) did not improve further the hemagglutination inhibitory properties. The next generations of glycoclusters have therefore incorporated different linkers for an easy access of the bulky lectins to several simultaneous carbohydrate epitopes. A combination of glycerol and ethylene glycol (Table 6, entry 70) was not beneficial and provided only a 10-fold improvement versus αManOMe as evaluated by ELISA.281 A series of trivalent mannosylated dendrons was synthesized and assayed against T

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hazardous properties of such tetra-azido-pentaerythritol. Meanwhile, several glycoclusters incorporating short287 (Table 6, entry 74) and long288 (Table 6, entry 75) linkers were synthesized using pentaerythritol. While the binding to FimH can be readily improved through the “cluster effect”, further enhancements could be obtained using aromatic aglycons in synergy with multivalency using pentaerythritol289 (Table 6, entry 76) or a peptide scaffold290−292 (Table 6, entries 77,78). Carbohydrates were used as core scaffolds for the design of multivalent ligands of FimH. Allylated carbohydrate precursors provided a general access to glycoclusters and glycodendrimers through hydroxylation/glycosylation conjugation strategy and thiol−ene “click” chemistry.293 Tetra-294 (Table 6, entry 79), undeca-295 (Table 6, entry 80), and dodecavalent296 (Table 6, entry 81) glycoclusters displayed rather similar inhibitory properties toward FimH as measured by ELISA. Azido-functionalized maltotriose was conjugated to alkynylated mannosides (Table 6, entry 82), and the resulting trivalent glycocluster displayed high affinity toward FimH.297 The reducing end of maltotriose could be further derivatized with a fluorescent dye to demonstrate capture and cross-linking of E. coli in solution. Presentation of the same heptyl mannopyranoside epitope on a cyclic heptavalent βcyclodextrin scaffold298 (Table 6, entry 83) provided Kd values measured by ITC similar to the maltotriose glycoclusters. The cyclodextrin core allowed for the measurement of an improvement in vivo through multivalency, which has rarely been reported. Indeed, these glycoclusters were validated in mice models for the treatment of urinary tract infections through intravenous injections rather than oral administration. The decavalent pillar[5]arene-based mannosylated glycocluster299 (Table 6, entry 84) distributes 10 mannose epitopes on a narrow central scaffold, and the affinity toward FimH is among the best observed to date. Increasing the valency to 12 on a spherical fullerene core300 (Table 6, entry 85) provided another potent ligand of FimH, while a hexadecavalent peptide-based glycocluster301 (Table 6, entry 86) did not prove more beneficial. Higher valency could be reached using a polylysine dendrimer (valency 16) or neoglycoproteins302 (valency 11−35) but also a pseudopolyrotaxane composed of mannosylated curcurbit[6]uril units threaded on a polyviologen303 (valency 110) with nanomolar affinity toward FimH.

discussed in detail in this Review but must be considered when designing such multivalent high affinity lectin ligands. 4.1. Application to the Shiga Toxin AB5 System

Shiga toxin (Stx) is another member of the AB5 toxins described above (see section 3.5).219 This virulence factor is produced by Shigella dysenteriae and by Shiga toxigenic E. coli (STEC) for which it is also related as verotoxin. The associated symptoms include diarrhea and hemorrhagic colitis but could also result in life-threatening hemolytic uremic syndrome (HUS) that occurs frequently in developing countries.304 Stx is specific for the αGal(1,4)Gal disaccharide that is the terminal part of globotriaosylceramide Gb3.305,306 The crystal structure of E. coli Stx complexed with an analogue of Gb3 trisaccharide (Figure 22) revealed one main high affinity binding site and two additional subsites with lower affinity.307

4. MULTIVALENT GLYCOCONJUGATES AS HIGH AFFINITY LIGANDS OF LECTINS The design of synthetic multivalent ligands of lectins has been conceptually inspired by the multivalent aspects found in nature’s way of merging together several moderate to weak monovalent interactions into a significantly stronger and more complex multivalent binding system, triggering biological events (e.g., viral or bacterial adhesion to a host cell or signal transduction). Chemists usually seek for the highest affinity ligand for a specific lectin, which has generally been obtained with the synergistic chelation of several binding sites simultaneously. The geometry of the central core scaffold, the valency number, and the nature and length of the spacer arm greatly influence the topology of the resulting macromolecule and consequently the expected binding properties. Importantly, the chemical synthetic approach chosen for the conjugation of building blocks into a multivalent architecture is critical because several reactions are performed at once on a central scaffold, and therefore high yields, easy purification, and complete chemo-, regio-, and/or stereoselectivities must be obtained. The synthetic aspects will not be

Figure 22. (Top and middle) Two orthogonal views of pentamer of subunit B from shiga toxin complexed with the multivalent starfish ligand (PDB code 1QNU). 308 (Bottom) Close view of the oligosaccharide binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, and hydrogen bonds by dashed lines. U

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Table 7. Multivalent Ligands of Stx1 and Stx2

87).308 The designed so-called “starfish” glycodendrimer displayed IC50 values in the subnanomolar range measured by ELLA, which represents an outstanding 8.75 × 106-fold increase in potency (β) when compared to the natural ligand. This spectacular potency was further rationalized through crystallographic studies in which two B5 pentamers were associated with the 10 epitopes of the “starfish” glycodendrimer. The structure demonstrated the presence of galactosylated ligands in the five primary binding sites of the pentamer (Figure 22).308 The core

The oligosaccharide moiety of the natural Gb3 ligand of Stx, the Galα(1,4)Galβ(1,4)Glc trisaccharide, was chosen as the recognition unit in most of the strategies toward multivalent Stx ligands. For instance, polyanionic glycopolymers were used for the detection of Stx1 and Stx2 on a glycochip,309 while a fluorescent polymer displayed binding properties toward Stx1 as well as binding to E. coli.310 One landmark study in the field utilized a central pentavalent glucose core functionalized with 10 trisaccharide epitopes using a divalent dendron (Table 7, entry V

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Figure 23. (Left) Graphical representation of tetramer of LecA from P. aeruginosa in complex with p-nitrophenyl β-D-galactopyranoside (PDB code 3ZYF).335 (Right) Close view of the galactose binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, calcium ions by spheres, and hydrogen bonds by dashed lines.

against E. coli infection by oral administration.323 Chitosan was grafted with Gb3 epitopes using reductive amination to afford a globotriose-chitosan glycopolymer (Table 7, entry 94) displaying nanomolar affinity toward Stx1 and submicrolar affinities toward Stx2.324 In vivo experiments demonstrated effective protection against bacterial infection, and these conjugates appear as potential agents against STEC disease. Glycopolydiacetylene nanoparticles using the disaccharide Galα(1,4)Gal epitope were designed as a highly selective, rapid, sensitive, and quantitative detection of STEC.325 Gold nanoparticles could reach much higher avidities toward Stx326 as revealed by the picomolar binding constants measured for the Gb3-functionalized GNPs (Table 7, entry 95).327 This result provides the highest relative potency (β) to date in comparison to the natural monovalent ligand Gb3, although using a multivalent scaffold with nearly 2000 epitopes on its periphery. Such hyper-avidity was applied to the purification of Stx from bacterial extracts. Carbosilane glycodendrimers328 incorporating six Gb3 units (Table 7, entry 96) displayed micromolar affinity toward Stx1.329 These glycoconjugates prevented incorporation of toxins into cells and protected mice from lethal infections in vivo. Increasing the valency to 36 epitopes (Table 7, entry 97) provided nanomolar Stx1 and Stx2 ligands with protective effect in vivo.330 A series of multivalent systems displaying Gb3 epitopes have been designed, and clinical trials up to Phase 3 were performed.331 While the binding to Stx could always be demonstrated with high affinities, the clinical trials indicated that oral therapy did not always diminish the severity of the disease (HUS). In vivo experimentation is therefore highly challenging in this field, and several high affinity ligands of Stx failed. Stx2 is more closely related to the development of HUS, and some studies also focused on the differentiation of Stx1 and Stx2.332 More recently, the discovery of novel Stx2 ligands was greatly accelerated by the design of a microtiter-plate screening of a library of Gb3 analogues with modifications at the 2-position on the nonreducing terminal galactose residue.333 The method is general and provides data even for low affinity ligands that would require multivalency to reach higher and useful avidities.

scaffold of this multivalent ligand was not resolved in the crystal structure and had to be modeled. It could then be demonstrated that five trisaccharides bind to a single B5 pentamers, while the other five Gb3 residues interact with another B5 pentamer in a sandwich-like system. The design of such anti-infective agents against Shiga toxins requires the action of ligands against Stx1 and Stx2.311 The “starfish” glycodendrimer was active against Stx1 but not as efficiently against Stx2,308 and, unfortunately, this system did not perform as well as expected in mice infection models.311 The so-called “daisy” glycodendrimer312,313 was then designed (Table 7, entry 88) as a variation of the “starfish” ligand with conjugation through the anomeric position of the carbohydrate epitope and with a different tether link. This “daisy” glycodendrimer provided protection against infections mediated by both Stx1 and Stx2.311 Further studies focused on the influence of the linker arm and multivalent presentation of the epitope.91,314 Another strategy was designed from heterobifunctional multivalent ligands in which one binding epitope would target the Stx, while the second moiety would interact with another protein causing aggregation. The Gb3 trisaccharide was conjugated through its anomeric position with a cyclic pyruvate of glycerol (Table 7, entry 89) used as a ligand for serum amyloid P (SAP) and assembled in a pentavalent heterobifunctional glycocluster.315 SAP is a protein with protective activity against Stx2-bacterial infection.316−320 IC50 values toward Stx1 were in the high micromolar range, while a low micromolar activity could be measured in the presence of SAP, which preorganized the glycocluster for an improved binding with Stx1. Following that result, polyacrylamide-based glycopolymers were designed for incorporating the two recognition motifs either on two different monomers (Table 7, entry 90) or on a single building block320 through a 1,2-bicyclic acetal glucose derivative (Table 7, entry 91).321 While the copolymer displayed similar inhibitory potencies in the nanomolar range with or without SAP, in the case of the hybrid trisaccharide, the addition of SAP caused a 105fold increase in inhibitory potency toward Stx1. Meanwhile, this glycopolymer was quite efficient in vivo against E. coli bacterial infection in a transgenic mice model expressing human SAP. The Gb3 trisaccharide was also copolymerized with acrylamide using a 10% load (Table 7, entry 92), and IC50 values in the micromolar range were obtained using a cell-based assay.322 The same polymeric scaffold with only the Gb3 unit polymerized (Table 7, entry 93) provided submicromolar affinities against both Stx1 and Stx2 as measured by SPR but also protection

4.2. Application to the Pseudomonas aeruginosa Lectin A (LecA or PA-IL)

Among its adhesion and virulence arsenal, Pseudomonas aeruginosa utilizes two soluble lectins (see section 3.2.), including LecA (PA-IL), a β-galactoside binding lectin.141,142 Structural W

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Table 8. LecA Mono- and Multivalent Ligands

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Table 8. continued

multivalent scaffold,343,344 and the different topological isomers were assayed as LecA ligands. The 1,3-alternate conformation proved optimal for binding to LecA71 (Table 8, entry 105). AFM studies72,73 helped to propose a chelate binding model for such lectin−carbohydrate multivalent interactions. Further design focused on modifications of the spacer arm to introduce one amide bond345 (Table 8, entry 106). Shorter spacer arms prevented the binding to LecA, while another lectin was still able to bind to the galactose epitopes.346 Further investigations toward the influence of the core’s topology included porphyrin, β-peptoids (linear or cyclic), and yielded efficient LecA ligands albeit with not so high affinity.347 Nevertheless, the hexavalent calix[6]arene-based glycocluster (Table 8, entry 107) displayed nanomolar affinity toward the lectin, therefore being among the most potent LecA ligand. Meanwhile, porphyrin-based glycoclusters could be applied to the nanoelectronic detection of lectins in a field-effect transistor using carbon nanotubes or graphene.348,349 A nonavalent C-galactosylated glycocluster centered on a benzene core (Table 8, entry 108) displayed nanomolar affinity toward LecA, while dendrimers with higher valencies could not be studied due to their poor solubility.350 Further increase in valency could be obtained using fullerene hexakis-adducts351 providing a dodecavalent glycocluster352 (Table 8, entry 109) with nanomolar binding to LecA. The conjugation of a total 24 galactosides on a hexasubstituted benzene-based core led to yet another nanomolar LecA ligand (Table 8, entry 110) and using a combination of thiol−ene and SN2 reactions.353 Higher valencies could be reached with glyconanoparticles354,355 to afford a potent low nanomolar LecA ligand356 (Table 8, entry 111) along with the discussion of the influence of ligand presentation density on the recognition by the lectin. Poly(phenylacetylene) was used as a polymeric scaffold for the design of glycopolymers, and the binding toward several lectins was reported.357 The α-galactoside with an aromatic aglycon was identified as the best ligand in the study (Table 8, entry 112). The potency improvement was remarkable through HIA but rather limited when measured by ITC.357 This example again highlights the importance of combining several bioanalytical techniques for the careful study of multivalent

studies demonstrated the presence of a bridging calcium ion in the carbohydrate binding site.334 LecA and Stx share the same glycan specificity on host tissue, both binding to the αGal(1,4)Gal disaccharide of globotriaosylceramide Gb3.137 LecA displays high affinity for α-functionalized saccharides, but the use of synthetic carbohydrates demonstrated a preference for β-aryl galactosides (Figure 23). The investigation of the structure−activity relationship for the design of high affinity LecA glycomimetics identified aromatic aglycons as hydrophobic capable of favorable contacts with the lectin. The 2-naphthyl residue was used in two parallel studies along with libraries of aromatic O-336 (Table 8, entry 98) or Sgalactosides337 (Table 8, entry 99). The crystallographic data of the ligands in complex with the lectin demonstrated a CH−π “Tshape” interaction between His50 and the aromatic ring contributing to the improved binding properties. While derivatization of the 2-naphthyl moiety into multivalent glycoclusters has not been investigated yet, the phenyl aglycon was reported in several cases for the design of potent LecA ligands. The glycopeptide combinatorial approach used for LecB was also applied to LecA and identified a high affinity monovalent β-galactoside338 (Table 8, entry 100). The similar aromatic aglycon displayed in a tetravalent glycopeptide scaffold (Table 8, entry 101) provided a strong enhancement of binding toward LecA reaching nanomolar affinity measured by ITC.335 Similar data could be obtained using a β-aryl galactoside and a cyclic tetra-glucosamine core (Table 8, entry 102), thus providing another nanomolar LecA ligand.339 A phosphodiester-mannose-based scaffold was reported using an aromatic aglycon340 (Table 8, entry 103), and the octavalent glycocluster obtained displayed greatly improved affinity in comparison to a monovalent reference galactoside as measured by a reverse ELLA on microarray.103 In a similar microarray study,341 the affinity could be modulated by both the charge of the scaffold and the topology of the glycoclusters. Resorcin[4]arene-based glycoclusters (Table 8, entry 104) did not displayed high affinity toward LecA, although these macromolecules could be synthesized with two different topologies.342 On the opposite, calix[4]arene was used as a Y

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lectin−carbohydrate interactions. Another synthetic glycopolymeric material was recently reported as inhibiting P. aeruginosa biofilm formation, although the interactions with LecA (or LecB) were not characterized.358 Finally, the recent rational design of divalent ligands359 provided the best ligand to date (Table 8, entries 113,114) with a Kd value of 28 nM toward LecA.360 The study focused on the design of a spacer arm resulting in improved binding properties relying on rigidity. The spacer arm incorporated rigid glucose units connected through triazole moieties that compared favorably to flexible oligoethylene glycols. The divalent ligand could be rationalized to bind in a “perfect” chelate binding mode with both galactosides in the adjacent binding sites of a single LecA tetramer using docking studies.360 Very recently, 1,3-alternate galactosylated and fucosylated glycoclusters were investigated in biological systems. The characterization of their inhibitory properties on Pseudomonas aeruginosa aggregation, biofilm formation, adhesion on epithelial cells, and destruction of alveolar tissues was performed. The antiadhesive properties of the designed glycoclusters were demonstrated through several in vitro bioassays. An in vivo mouse model of lung infection provided an almost complete protection against coinstillation of Pseudomonas aeruginosa in mice lungs with the designed glycoclusters. Such multivalent ligands now appear as promising drug candidates for the treatment of bacterial infections.361 4.3. Application to the Inhibition of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin (DC-SIGN)

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a C-type l lectin involved in the recognition of viruses (e.g., HIV and Ebola virus) or other pathogens (e.g., Leishmania and Candida species).362 This membrane-protein is present on the dendritic cells in the mucosa and associates as tetramers, presenting four carbohydrate-binding domains on the top of a long stem.363 The CRD of DC-SIGN is calcium dependent and is specific for mannose and fucose, with higher affinity toward Lewis oligosaccharides (Figure 24).364 DC-SIGN is involved in innate immunity because it binds various microorganisms. However, this function has been hijacked by HIV. DC-SIGN transports the virus to the lymphoid organ through binding to gp120, playing therefore a crucial role in the infection process at mucosa level.365 Inhibitors of DC-SIGN are therefore of high interest against HIV infection.366 A noncarbohydrate inhibitor of DC-SIGN (Table 9, entry 115) was identified in a high-throughput assay of 36 000 molecules.368 Because the initial evaluation of the inhibitory potencies was accomplished in a competitive fluorescence assay against a mannosylated BSA neoglycoprotein, the inhibitor is assumed to interact at the binding site of DC-SIGN, although further investigations are still ongoing. As a continuation of this work, a series of more than 20 quinoxalinones were tested, providing a submicromolar IC50 value (Table 9, entry 116).369 The compound was also evaluated in a cellular assay thanks to flow cytometry and was demonstrated to block DC-SIGNmediated internalization. Such results are important for the better understanding of DC-SIGN implications in pathogenesis and immune function. A novel high-troughput screening assay was also developed for the rapid and efficient identification of inhibitors of the HIV gp120 glycoprotein interactions with DCSIGN.370

Figure 24. (Top) Tetramer of DC-SIGN containing the CRD and part of the neck (PDB code 1XAR) with sodium ions replacing calcium.363 (Middle) CRD of DC-SIGN complexed with a glycomimetic ligand (PDB code 2XR5).367 (Bottom) Close view of the mannose binding site. Peptide chain represented by ribbon, oligosaccharide by sticks, calcium ions by spheres, and hydrogen bonds by dashed lines.

The design of DC-SIGN high affinity ligands can be approached through glycomimetics of the oligomannoside natural ligand (Man)9(GlcNAc)2, which mimics the terminal two or three mannose residues.371 The Lewisx trisaccharide Galβ(1,4)[Fucα(1,3)]GlcNAc was reported as a ligand of DCSIGN, indicating the importance of not only mannose but also the fucose epitope in the binding to the protein.372 The design of Lex glycomimetics with a fucosylamide anchor and two additional cyclohexane-based moieties mimicking the galactose and GlcNAc residues (Table 9, entry 117) yielded a moderately potent DC-SIGN ligand.373 Another analogue of the Lex trisaccharide was designed (Table 9, entry 118) incorporating a cyclohexane moiety mimicking the GlcNAc residue and a phenol in place of the Gal epitope.374 NMR studies confirmed the binding to DC-SIGN mainly through interactions with the fucose residue, and the aromatic moiety provides additional contacts with the protein, thus increasing the affinity.375 The conjugation of such ligand to a tetravalent pentaerythritol-based core provided a glycocluster (Table 9, entry 119) displaying improved inhibition toward DC-SIGN but yet in the same range as the natural Lewisx ligand.376 A similar approach was used for the design of a linear trimannoside analogue (Table 9, entry 120) with activity against HIV viral infection in a cellular assay.377 The same monovalent ligand was then conjugated to a tetravalent scaffold, and the Z

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Table 9. DC-SIGN Ligands

AA

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Table 9. continued

and the resulting neoglycoprotein acts as a DC-SIGN agonist eliciting lectin-mediated signaling in cellular assays.391 The mannose epitope was used in a glycolipid strategy for the design of anti-HIV agents. When a single mannose moiety was associated with a lipid chain (Table 9, entry 129), the enhanced affinity toward DC-SIGN did not require multivalent presentation, and these glycolipids could reduce HIV infection in the low micromolar range.392 In addition, a trivalent glycolipid with unsaturated lipid chain (Table 9, entry 130) such as 1,3-diyne displayed similar affinity toward DC-SIGN.393 Nevertheless, the 1,3-diyne can be polymerized to provide polymeric micelles, which did not act as antivirals, while the dynamic micelles did prevent HIV infection. This result illustrates the influence of dynamic versus rigid multivalent systems on the affinity and biological activity. A similar trimannosylated dendron was incorporated into a nonavalent glycodendron (Table 9, entry 131) that displayed nanomolar IC50 values toward DC-SIGN, which is 106-fold better than mannose.394 This ligand was also identified as a potential epitope for HIV vaccine development.395 This type of nonavalent glycodendron functionalized with fucose, mannose, or trimannosides was also labeled with a fluorescent dye, and cellular internalization could be demonstrated.396 Nevertheless, no induction of inflammatory or noninflammatory cytokines could be detected. Mannosylated gold glyconanoparticles (Au-GNPs) provided access to larger valencies up to 50 or 60 copies of the saccharide. The incorporation of 1,2-mannobioside epitopes into Au-GNP (Table 9, entry 132) totally inhibited the interaction of DCSIGN to gp120 at a concentration (C100) of 4.7 μM in a viral infection model assay.397 A tetrasaccharide Manα(1,2)Manα(1,2)Manα(1,3)Man was used in combination with of a small amount of glucose in the composition of a mannosylated AuGNP (Table 9, entry 133) to observe anti-HIV infection activities on human cells with IC50 values in the subnanomolar range.398 The same mannosylated Au-GNP incorporation of a fluorescent label was used in cellular assays demonstrating their uptake in cells and colocalized with DC-SIGN in early endosomes, thus explaining their ability to block HIV infection in vitro on human T cells.399 Galactofuranose-coated Au-GNP were recently demonstrated to elicit a pro-inflammatory response (IL-6 and TNF-α) in human dendritic cells through recognition by DC-SIGN.400 This is a rare example of the role of galactofuranose in binding to DC-SIGN.

resulting glycocluster (Table 9, entry 121) displayed improved binding properties and also better inhibition of DC-SIGNmediated HIV infection.378 The same linear trimannoside analogue was conjugated to a Boltorn H30 dendrimer379 to obtain a glycodendrimer (Table 9, entry 122) with 30−32 copies of the synthetic epitope.380 While the mannosylated glycodendrimers were active against Ebola or HIV viral infection,381,382 the present glycodendrimer (Table 9, entry 122) was identified as a nanomolar inhibitor of Ebola virus infection.380 Protection against Ebola infection was also achieved at nanomolar concentrations using a 36-valent fullerene-based.383 The 1,2-mannobioside disaccharide unit Manα(1,2)Man is probably one of the minimal epitopes for binding to DC-SIGN. Following the same strategy, mimetics of this disaccharide using a mannoside with a cyclohexane-based aglycon (Table 9, entry 123) displayed micromolar activity against Ebola viral infection.384 The rationalization of the binding properties of such glycomimetic ligand could be addressed on the basis of crystallographic data of the ligand in the binding site of DCSIGN.385 Modification of the ester moieties into amides generated a low micromolar DC-SIGN ligand386 (Table 9, entry 124), while a divalent analogue (Table 9, entry 125) did not improve further the binding properties.387 An hexavalent bisamide derivative was also reported for micromolar inhibition against HIV infection but also Dengue virus.388 A dynamic system was reported in which a library of 37 485 pairs of nucleic acid conjugated to the 1,2-mannobioside (Table 9, entry 126) was screened against DC-SIGN and provided nanomolar ligands.389 This example is an illustration of the influence of self-assembly for the design of potent lectin ligands. Shikimic acid can be considered as a chiral scaffold matching the stereochemical organization of the 2-, 3-, and 4-positions of the mannose hydroxyl groups. Derivatization of this molecular core structure provided a monovalent glycomimetic (Table 9, entry 127) with millimolar IC50 values toward DC-SIGN.390 NMR HSQC experiments demonstrated that the glycomimetic binds at the same site as mannosides and interacts with the same amino-acid residues.391 Controlled polymerization using ringopening metathesis polymerization (ROMP) of norbornenebased monomers provided a glycopolymer with controlled valency of nearly seven copies of the glycomimetic (Table 9, entry 128) with micromolar IC50 values.390 Sixteen copies of the same shikimic acid-based glycomimetic were conjugated to BSA, AB

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properties is sometimes counter-productive because saturation can occur quite rapidly when reaching valencies of 4−6 with higher valencies being less relevant. The proper spacer arm with optimal rigidity and solubility is of prime importance in such design with aromatic aglycons being sometimes very beneficial. Also, a tremendous complexity can arise from interacting multivalent partners in terms of competing mechanisms of interactions and regarding the selectivity toward the desired target. This increases the difficulty for the potential development of specific and efficient chemical tools and drug candidates in complex biological environment. Nevertheless, glycoclusters and small dendrimers have now been demonstrated as promising antiadhesive compounds against several pathogens. If the monovalent glycomimetic and the multivalent approaches can reach similar efficiencies in terms of affinity and selectivity, they still display some significant and useful differences that can be highlighted by the evolutionary conserved coexistence of both types of interactions in all living systems. When targeting a lectin and engaging in the development of potent ligands, choosing between glycomimetic and multivalency-based approaches is not trivial and requires a strong knowledge of the protein along with defined objectives regarding the perturbation that one intends to create for the studied system. Even if competing mechanisms of interaction and aggregative phenomenon can be challenging and tedious to the experimentator, they remain physiologically relevant, and neglecting the multivalency of most carbohydrate−lectin interactions would undoubtedly provide an incomplete overview of the science at stakes. Acquiring knowledge and developing ways and tools to study the characteristics of the actual multivalent presentation of carbohydrates by cellular membranes is certainly one of the most difficult challenges in this field. However, there is little doubt that tremendous achievements could result from this knowledge, for example, through the design of optimized multivalent architectures that are truly based on natural arrangements. The fate of each drug candidate or chemical tools will most likely be decided by in vivo efficiency, and researchers are now advancing in this direction with some pathogens and lectin blockers. The evident combination of both approaches with the multivalent presentation of optimized glycomimetic units has recently gained increasing interest. Such a hybrid approach will undoubtedly provide the greatest success of our field because both approaches can provide affinity and selectivity improvement in a synergetic manner. However, bringing multivalency and medicinal chemistry-based glycomimetic approaches together results in a tremendous number of combinations. Therefore, developing efficient hybrid structures could not make the economy of a careful optimization of both the glycomimetic recognition unit, the multifunctional presenting core, and the tether links, all three moieties playing a crucial role in such design. No real opposition can be drawn between monovalent and multivalent ligands of lectin. Each approach has demonstrated its potential to reach convincing drug candidates. The fate of each drug candidate will most likely be decided by in vivo experimentation, and researchers are now advancing in this direction with some pathogens and lectin blockers. Meanwhile, a combination of a potent monovalent ligand conjugated to a relevant multivalent core scaffold would probably provide a synergy between each approach, and such research efforts still have to be implemented.

Similar valencies were also obtained using glycopolymers (Table 9, entry 134) synthesized using a combination of coppermediated living radical polymerization and azide−alkyne 1,3dipolar cycloaddition.401 The fully mannosylated polymer could prevent interactions between DC-SIGN and the HIV viral envelope glycoprotein gp120. Introduction of increasing proportions of galactose in the polymeric constitution decreased the binding affinity. Finally, virus-like glycodendrinanoparticles were synthesized to afford polyvalent particles with picomolar activity against Ebola viral infection illustrating the concept of “nested polyvalency”.98 A major aspect of blocking HIV infection through DC-SIGN high affinity ligands is to have selectivity for DC-SIGN versus langerin. Langerin is a mannose-specific C-type lectin expressed at the surface of Langerhans cells402 and is present in the same environment as DC-SIGN. Moreover, langerin has a protective action against HIV infection,403 and the design of DC-SIGN ligand should not interfere with langerin.404 DC-SIGN to langerin selectivity represents therefore a priority for the selection of a lead compound against HIV infection.387 A recent study reported the binding properties of two active compounds chemically analogous toward DC-SIGN.405 This study is probably one of the few examples in which the compound with the lower apparent binding profile was still investigated in vivo and proved to be the optimal lead for further drug development. This is a clear example of drug design and compound selection when approaching in vivo experimentation and when moderate ligands can find their way out of bioanalytical in vitro techniques to the real world.

5. CONCLUSION Interfering with the binding of lectin to its receptor on host cells or perturbing some lectins’ natural biological action can be achieved through the design and synthesis of glycomimetics with high affinity and specificity. These strategies used the medicinal chemistry approaches that have successfully been applied to a number of proteins and enzyme targets (e.g., kinases, glycosidases). The description of a large number of crystal structures and specificity data for lectins allowed the rational design of high affinity monovalent ligands sometimes based on predictive studies (e.g., molecular modeling or docking). The inhibitory potency toward a specific process and the binding properties of the interaction of these monovalent ligands can be readily studied using standard bioanalytical techniques including ITC, HIA, ELLA, and SPR as well as cocrystallization and NMR. The best monovalent ligands obtained from these investigations were applied to in vivo experimentations, and approval from drug regulatory authorities (e.g., Food and Drugs Administration, FDA in the U.S. or the European Medicines Agency, EMA in Europe) can be optimiztically foreseen. The most advanced research projects in this field have identified “lead” compounds and are now reporting on their pharmacological properties (e.g., solubility, toxicity, pharmacokinetics). Some of these molecules might even enter preclinical or clinical trials. The design of multivalent ligands usually provides higher affinities, sometimes even using very simple recognition motifs such as the terminal monosaccharide of the natural ligand. Yet the careful selection of multivalent core scaffolds and the conjugation methodology for the assembly of the carbohydrate epitope to the core is important for the success of such a strategy in terms of both synthetic efficiency and biological properties. The general idea of increasing the valency to improve binding AC

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AUTHOR INFORMATION

human glycoconjugates, design of glycocompounds with anti-infectious properties, and engineering of neolectins with controlled specificity.

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Sébastien Vidal currently holds a CNRS position at University of Lyon. He was born in Montpellier (France) in 1974. He received his Ph.D. in Organic Chemistry (2000) from the University of Montpellier (France). He studied under the direction of Professor Jean-Louis Montero and synthesized mannose 6-phosphate analogues for drug delivery applications. He then moved to the group of Sir J. Fraser Stoddart as a postdoctoral fellow at UCLA to study the synthesis and characterization of glycodendrimers but also the design of pseudorotaxanes and stayed there for two and a half years. In 2003, he moved to the National Renewable Energy Laboratory (NREL, Golden, CO) and studied with Prof Joseph J. Bozell the combination of organometallic and carbohydrate chemistries for the design of new reactions involving both aspects of modern organic synthesis. After one year, he joined the group of Prof. Peter G. Goekjian at University of Lyon in 2004 where he started as a postdoctoral fellow and successfully applied to a CNRS position as “Chargé de Recherche”. He then started his own research projects dealing with carbohydrate chemistry and applications in biology. The main topics covered in his research are the design of glycoclusters for anti-adhesive strategy against bacterial infections but also enzyme inhibitors targeting glycogen phosphorylase with applications in type 2 diabetes (hypoglycemic drugs) or glycosyltransferases such as OGT. He has co-authored 70 publications from his collaborative research.

Samy Cecioni graduated (Master degree in organic chemistry) from Université Claude Bernard Lyon 1 and concurrently received a Diplôme d’Ingénieur from CPE Lyon. He then received his Ph.D. under the direction of Dr. Jean-Pierre Praly and Dr. Anne Imberty. His graduate work focused on the study of multivalency in carbohydrate−lectin interactions, with the synthesis of glycoclusters and their evaluation against pathogen lectins. He is currently a CIHR-funded postdoctoral researcher in the Laboratory of Chemical Glycobiology of Pr. David Vocadlo at Simon Fraser University, Burnaby, Canada. His current research interests include the development of chemical tools for the study of glycosylation in live cells.

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Dr. Imberty is Research Director at the Centre de Recherches sur les Macromolécules Végétales (CERMAV), affiliated to the Centre National de la Recherche Scientifique (CNRS) based at Grenoble, France. She graduated in biology from Ecole Normale Supérieure in Paris. In 1984, she joined the Centre National de la Recherche Scientifique in Grenoble and did her Ph.D. on starch structure. She started modeling studies of protein−carbohydrate interaction during her post-doc in Toronto. She received several national and international awards, including the Roy Whistler Award from International Carbohydrate Organisation in 2004, silver medal from CNRS in 2013, and the Legion d’Honneur in 2014. She has published more than 250 scientific papers. Her research interests are in the field of structural glycosciences. Her current interest is the characterization of the molecular basis of recognition between lectins from pathogens and AD

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