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Strategies for the Development of Glycomimetic Drug Candidates pharmaceuticals Review Strategies for the Development of Glycomimetic Drug Candidates Rachel Hevey Molecular Pharmacy, Dept. Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland; [email protected] Received: 15 March 2019; Accepted: 9 April 2019; Published: 11 April 2019 Abstract: Carbohydrates are a structurally-diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Many diseases have been correlated with changes in the composition of cell-surface glycans, highlighting their potential as a therapeutic target. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties. To enhance their usefulness as drug candidates, ‘glycomimetics’ have been developed: more drug-like compounds which mimic the structure and function of native carbohydrates. Approaches to improve binding affinities (e.g., deoxygenation, pre-organization) and pharmacokinetic properties (e.g., limiting metabolic degradation, improving permeability) have been highlighted in this review, accompanied by relevant examples. By utilizing these strategies, high-affinity ligands with optimized properties can be rationally designed and used to address therapies for novel carbohydrate-binding targets. Keywords: carbohydrate; glycomimetic; drug development; lectin; lead optimization; binding affinity 1. Introduction As one of the most abundant natural products, carbohydrates play many integral roles throughout our environment, for example as a metabolic energy source, a structural component of cell walls, and cellular recognition. They are present as various biological conjugates, including glycoproteins, proteoglycans, and glycolipids, and typically form a thick layer at the cell surface of approximately 10–100 Å which is referred to as the ‘glycocalyx’ [1,2]. This expression at the extracellular surface makes them ideally suited for interactions with neighboring cells and biomolecules. In mammals, oligosaccharides are comprised of unique combinations of a defined group of monosaccharide residues which exhibit impressive structural complexity [3]. In contrast to amino acids and nucleotides which are typically assembled in a linear fashion, carbohydrates can form both linear and branched structures with contiguous stereocenters, affording a diverse array of structures. In addition to varying stereochemistry and regiochemistry of their glycosidic linkages, the monosaccharides forming these complex structures can also vary in their ring size (e.g., furanose, pyranose) and are often further modified (e.g., acetylation, sulfation, methylation) (Figure1). The syntheses of oligosaccharides in vivo are accomplished by carbohydrate-processing enzymes: (i) glycosylases, which hydrolyze terminal residues; (ii) glycosyltransferases, which add residues to an existing structure; and (iii) other glycan-processing enzymes, such as sulfotransferases, which structurally fine tune individual functional groups. Pharmaceuticals 2019, 12, 55; doi:10.3390/ph12020055 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2019, 12, 55 2 of 26 Pharmaceuticals 2019, 12, x 2 of 26 HO OH OH HO O HO OH O O O HO HO HO OH O HO O HO O O HO O HO OH HO OH HO HO O OH HO O HO O OH amylose HO 2α-mannobiose 3α-mannobiose poly-α-(1→4)-Glc HO O (b) OH OH OH OAc O CO H O O OH 2 HO O O O HO O O HO OH HO O O OR OH OH AcHN cellulose HO β → poly- -(1 4)-Glc pyranose furanose 9-O-Ac-Neu5Ac (a) (d) (c) Figure 1. StructuralStructural variation variation in in glycans glycans arises arises from from differences differences in: in:(a) (anomerica) anomeric stereochemistry; stereochemistry; (b) (regiochemistryb) regiochemistry of linkages; of linkages; (c) ring (c) ring size; size; and and (d) (furtherd) further covalent covalent modifications. modifications. Carbohydrate structures structures attached attached to toprot proteinseins are commonly are commonly classified classified as either as O either-linkedO (e.g.,-linked to (e.g.,serine to or serine threonine or threonine amino acid amino side acid chains) side chains) or N-linked or N-linked (e.g., to (e.g., asparagine to asparagine side chains). side chains). The Thebiosyntheses biosyntheses of these of these two two groups groups occur occur via via two two distinct distinct mechanisms. mechanisms. OO-Linked-Linked glycans glycans are synthesized in a much moremore straightforwardstraightforward fashion:fashion: a monosaccharide is first first transferred to the SerSer/Thr/Thr sidechain and then other glycosyltransferases subsequently add to the structure, making it increasingly complex. In In contrast, the formation of N-linked glycans involves the initial assembly of a complex oligosaccharide onto a phospholipid scascaffffoldold (dolichyl pyrophosphate), which then gets transferred withinwithin the the endoplasmic endoplasmic reticulum reticulum to ato protein a protein asparagine asparagine residue; residue; the glycan the glycan is then is further then elaboratedfurther elaborated through through a combination a combination of glycosidases of glycosidases whichcan which partially can partially deconstruct deconstruct the original the original glycan construct,glycan construct, and glycosyltransferases and glycosyltransferases which add additionalwhich add sugar additional residues. Furthersugar functionalizationresidues. Further of thefunctionalization glycan can then of the occur glycan via the can addition then occur of acetate,via the addition sulfate, phosphate,of acetate, sulfate, or other phosphate, groups to or various other positionsgroups to ofvarious the oligosaccharide. positions of the oligosaccharide. Proteins which bind to carbohydratecarbohydrate ligands can be broadly classifiedclassified into enzymatic proteins (e.g., glycosidases, glycosyltransferases), lectins (n (non-enzymatic,on-enzymatic, signaling prot proteins),eins), or or glycosamino- glycosamino- glycan-binding proteins.proteins. Lectins Lectins play play a prominent a prominent role inrole host in recognition host recognition processes, processes, and are primarilyand are locatedprimarily at located the cell at surface the cell but surface can also but be can found also asbe soluble found as proteins. soluble Lectinsproteins can. Lectins be further can be classified further intoclassified various into sub-groups, various sub-groups, such as the such C-type as the lectins C-type (e.g., lectins selectins) (e.g., which selectins) require which Ca2 +requireions for Ca protein2+ ions bindingfor protein and binding play an and integral play rolean integral in intercellular role in intercellular adhesion and adhesion pathogen and recognition, pathogen orrecognition, I-type lectins or (e.g.,I-type Siglecs) lectins (e.g., which Siglecs) are part which of the are immunoglobulinpart of the immunoglobulin superfamily superfamily and are important and are important for immune for regulation.immune regulation. The affinities The ofaffinities carbohydrate-protein of carbohydrate-protein interactions interactions are characteristically are characteristically very weak, withvery dissociationweak, with dissociation constants (K dconstants) in the range (Kd) ofin micromolarthe range of to micromolar millimolar, whichto millimolar, has typically which been has attributed typically tobeen several attributed factors. to several Firstly, theyfactors. lack Firstly, hydrophobic they lack functional hydrophobic groups functional and are groups therefore and unable are therefore to form hydrophobicunable to form interactions hydrophobic with interactions the protein surface;with the hydrophobic protein surface; interactions hydrophobic are typically interactions a feature are oftypically high a ffia nityfeature interactions. of high affinity Secondly, interactions. their affinity Secondly, often relies their onaffinity hydrogen-bonding often relies on (H-bonding) hydrogen- interactionsbonding (H-bonding) with the protein interactions surface with and the they protein have surface a difficult and time they competing have a difficult with H-bonding time competing from bulkwith solvent.H-bonding Thirdly, from sincebulk solvent. the relatively Thirdly, shallow, since solvent-accessiblethe relatively shallow, protein solvent-accessible binding site and protein polar surfacebinding areasite and of the polar ligands surface both area form of the extensive ligands H-bonding both form networksextensive withH-bonding bulk solvent, networks this with needs bulk to besolvent, removed this priorneeds to to ligand-protein be removed associationprior to ligand-protein and results inassociation large enthalpic and results penalties in forlarge desolvation. enthalpic Finally,penalties flexibility for desolvation. in their structuresFinally, flexibility can result in in thei highr structures entropic penaltiescan result for in protein high entropic binding. penalties for protein binding. 1.1. Carbohydrates in Disease Carbohydrates play an important role in a number of biological processes, such as cell adhesion, inflammatory migration, host-pathogen recognition, immune activation, and cancer metastasis [4–6]. Many diseases have been correlated with changes in the composition of cell-surface glycans, a direct Pharmaceuticals 2019, 12, 55 3 of 26 1.1. Carbohydrates in Disease Carbohydrates play an important role in a number of biological processes, such as cell adhesion, inflammatory migration, host-pathogen recognition, immune activation, and cancer metastasis
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