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Multivalent Carbohydrate-Lectin Interactions: How Synthetic Chemistry Enables Insights Into Nanometric Recognition

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Multivalent Carbohydrate-Lectin Interactions: How Synthetic Chemistry Enables Insights Into Nanometric Recognition molecules Review Multivalent Carbohydrate-Lectin Interactions: How Synthetic Chemistry Enables Insights into Nanometric Recognition René Roy 1,*, Paul V. Murphy 2 and Hans-Joachim Gabius 3 1 Pharmaqam and Nanoqam, Department of Chemistry, University du Québec à Montréal, P. O. Box 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, Canada 2 School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland; [email protected] 3 Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, Veterinärstr. 13, München 80539, Germany; [email protected] * Correspondence: [email protected]; Tel.: +1-514-987-3000 (ext. 2546) Academic Editor: Trinidad Velasco-Torrijos Received: 7 April 2016; Accepted: 10 May 2016; Published: 13 May 2016 Abstract: Glycan recognition by sugar receptors (lectins) is intimately involved in many aspects of cell physiology. However, the factors explaining the exquisite selectivity of their functional pairing are not yet fully understood. Studies toward this aim will also help appraise the potential for lectin-directed drug design. With the network of adhesion/growth-regulatory galectins as therapeutic targets, the strategy to recruit synthetic chemistry to systematically elucidate structure-activity relationships is outlined, from monovalent compounds to glyco-clusters and glycodendrimers to biomimetic surfaces. The versatility of the synthetic procedures enables to take examining structural and spatial parameters, alone and in combination, to its limits, for example with the aim to produce inhibitors for distinct galectin(s) that exhibit minimal reactivity to other members of this group. Shaping spatial architectures similar to glycoconjugate aggregates, microdomains or vesicles provides attractive tools to disclose the often still hidden significance of nanometric aspects of the different modes of lectin design (sequence divergence at the lectin site, differences of spatial type of lectin-site presentation). Of note, testing the effectors alone or in combination simulating (patho)physiological conditions, is sure to bring about new insights into the cooperation between lectins and the regulation of their activity. Keywords: agglutinin; galectin; glycocluster; glycodendrimer; glycophane; glycoprotein; liposomes; oligosaccharides; sugar code 1. The Third Alphabet of Life Synergy, by teaming up chemistry with biosciences, can be expected to arise when the topic on which to apply complementarity of the disciplines is clearly defined. In principle, the chemical platform of life includes molecular alphabets, whose ‘letters’ are a toolbox to form ‘messages’ (or ‘words’) in the form of oligomers and polymers. “To an observer trying to obtain a bird’s eye view of the present state of biochemistry, or what is sometimes referred to as molecular biology, life may until very recently have seemed to depend on only two classes of compounds: nucleic acids and proteins” [1]. Their broad natural occurrence is shared by a third group, i.e., glycans. Present in Nature as polysaccharides such as chitin, or as part of cellular glycoconjugates, i.e., glycoproteins and glycolipids [2–13], their ubiquity and abundance have attracted interest to characterize rules of structural design, starting with the composition. This systematic work on material from pro- and eukaryotes step by step led to compiling the list of all individual building blocks, which form cellular glycocompounds. With the analogy Molecules 2016, 21, 629; doi:10.3390/molecules21050629 www.mdpi.com/journal/molecules Molecules 2016, 21, 629 2 of 35 Molecules 2016, 21, 629 2 of 36 eukaryotes step by step led to compiling the list of all individual building blocks, which form cellular glycocompounds. With the analogy to a molecular language in mind, this list constitutes the thirdto a molecular alphabet of language life, which in mind, complements this list constitutes the alphabets the of third nucleotides alphabet and of life, amino which acids complements (Figure 1). Asthe is alphabets common of for nucleotides amino acids and in amino proteins, acids substitutions (Figure1). As such is commonas phosphorylation for amino acids or sulfation in proteins, also broadensubstitutions the range such asof phosphorylationletters for glycans. or This sulfation use of also the broaden same principle the range of of post-synthetic letters for glycans. modifications This use underscoresof the same principlethe equivalence of post-synthetic of these modificationsalphabets with underscores respect to thetheir equivalence involvement of thesein the alphabets flow of withinformation respect from to their genes involvement to cellular in activities the flow [14,15]. of information from genes to cellular activities [14,15]. OH HO HO OH OH OH O O HO O Me O HO OH OH HO OH HO OH HO OH OH HO HO D-Glucose (Glc) D-Galactose (Gal) D-Mannose (Man) -L-Fucose (Fuc) OH HO OH O O HO O HO HO OH HO OH HO OH AcHN AcHN OH D-N-Acetylglucosamine (GlcNAc) D-N-Acetylgalactosamine (GalNAc) D-Xylose (Xyl) OH OH O CO2H HO C O HO2C O 2 HO OH HO OH OH OH HO HO HO O OH OH OH HO a b OH D-Glucuronic acid (GlcA) L-Iduronic acid (IdoA) L-Arabinose (Ara) HO H OH HO HO OH OH CO2H Me O HO O HO O OH HO CO2H OH AcHN OH HO OH -L-Rhamnose (Rha) 5-N-Acetyl- 2-Keto-3-deoxy-D- neuraminic acid (Neu5Ac) manno-octulosonic acid (Kdo) Figure 1. IllustrationIllustration of of the alphabet of thethe sugarsugar language.language. Structural representation, name and symbol as well as the set of known acceptor positionspositions (arrows) in glycoconjugates are given for each letter. Four sugars have L-configuration: fucose (6-deoxy-L-galactose), rhamnose (6-deoxy-L-mannose) letter. Four sugars have L-configuration: fucose (6-deoxy-L-galactose), rhamnose (6-deoxy-L-mannose) L and arabinose are introduced duringduring chain elongation, whereas L-iduronic acid (IdoA) results from post-synthetic epimerization of glucuronic acid at C-5. The 1C4 conformation1 of IdoA (a) is in equilibrium post-synthetic epimerization of glucuronic acid at C-5. The C4 conformation of IdoA (a) is in with the 2S0 form (b) 2in glycosaminoglycan chains, where this uronic acid can be 2-sulfated. All other equilibrium with the S0 form (b) in glycosaminoglycan chains, where this uronic acid can be 2-sulfated. Allletters other areletters D-sugars. are DNeu5Ac,-sugars. one Neu5Ac, of the onemore of than the more 50 sia thanlic acids, 50 sialic often acids, terminates often terminates sugar chains sugar in animalchains inglycoconjugates. animal glycoconjugates. Kdo is a constituent Kdo is a of constituent lipopolysaccharides of lipopolysaccharides in the cell walls in of the Gram-negative cell walls of bacteriaGram-negative and is bacteriaalso found and in is cell also wall found polysacchar in cell wallides polysaccharides of green algae of and green higher algae plants. and higher Foreign plants. to mammalianForeign to mammalian glycobiochemistry, glycobiochemistry, microbial polysacc microbialharides polysaccharides contain the containfuranose the ring furanose form of ring D-galactose form of andD-galactose also D/ andL-arabinose, also D/L -arabinose,then indicated then by indicated an italic by “ anf” italicderived “f” derivedfrom the from heterocyclus the heterocyclus furan. furan. The Theα-anomerα-anomer is prevalent is prevalent for the for pentose the pentose arabinose, arabinose, e.g., e.g.,in mycobacterial in mycobacterial cell wall cell wallarabinogalactan arabinogalactan and lipoarabinomannan.and lipoarabinomannan. β1-5/6-Linkedβ1-5/6-Linked galactofuranoside galactofuranoside is pr isesent present in inthe the arabinogalactan arabinogalactan and and the α1-3/6 linkage linkage in in lipopolysaccharides lipopolysaccharides (adapted (adapted from from [15]). [15]). Drawing on textbook knowledge, the consideration of availability of several hydroxyl groups for building the glycosidic bond lets the special talent of carbohydrates to encode bioinformation become obvious. In contrast to the fixed connecting points of nucleotides and amino acids, two Molecules 2016, 21, 629 3 of 36 monosaccharides can be covalently linked to yield a groups of isomers: the anomeric position and linkage points are the sources of variability. What initially appeared as a deterrent to work with glycans, that is the enormous structural variety unsurpassed among biopolymers that so fittingly is expressed in the term ‘complex carbohydrates’, was then realized to be the basis for enabling high-density coding. Ironically, what at first impeded smooth progress turned out to be a means to put signals for different aspects of cell sociology into a minimum of space, an amazing functional dimension of glycans [14,15]. Due to the growing realization of this potential developing tools for chemical analysis of glycans on all structural levels [16] is crucial to delineate structure-activity relationships. That “in many cases the real role of biological glycoconjugate glycans is still unknown and, in many cases, we are unable to answer the question: why are proteins and lipids glycosylated?” [17] and that “on the whole, the role of many glycans remains obscure and the subject of speculation or controversy” [17] is no longer valid. In fact, the sequence of glycans, as in proteins or nucleic acids, gives shape to these biomolecules, seemingly minor alterations acting like switches between conformations [18–22]. Of note, the often encountered limitations to intramolecular flexibility of biorelevant oligosaccharides,
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