chapter 2 - Bentham Science

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FOREWORD Attachment of carbohydrates in all its forms is a strategy exploited by both nature and those that study nature. Since the first reviews over 70 years ago the importance of this critically modulating and even defining role has long been recognized by who those study them. The very presence of carbohydrate units in naturally occurring structures and their mimetics has a dramatic effect on their physical, chemical and biological properties. Glycoscience is by necessity broad in the range of techniques that it encompasses and I have argued for over ten years that in this context the sometimesapplied and somewhat artificial distinction between "chemical" and "biological" techniques is unhelpful. This has never been the case – we are reaching a stage in the field where remarkable techniques are able to make even some very large naturally relevant glycoconjugates. Moreover, through these methods and the design of some remarkable molecular experimental approaches, we are using these glycoconjugates to unpick the many dazzling and exciting roles that carbohydrates play in Biology and Medicine. This book highlights this superbly. Drs Renaudet and Spinelli have assembled an outstanding collection of excellent and relevant reviews written by leading protagonists in the field that complement each other superbly. Together they provide a wonderful account of the current state-of-the-art. Vital current targets illustrate what might and will be achieved through both analysis and understanding. Many pathogens exploit the display of carbohydrates on host cell surfaces to gain entry. Imberty and Lindhorst, in their chapters, have described some of the most current and relevant examples. Integral to the approaches they have analyzed is a fundamental molecular analysis of the binding of sugars to proteins. This has been excellently amplified by the chapter of Goyer and Labbé, which describes some of the most pertinent quantitative techniques in current use, and by the several chapters that show how this understanding can be directly related to application. These include the design of inhibitors of bacterial toxins, superbly analyzed by Turnbull and Hayes, and ligands for the important mammalian galectins, the study of which Vidal summarizes superbly. Use of well-defined scaffolds is an essential element if this study and exploitation is to be precise. Various platforms have been analyzed here: fullerenes (Roy and Chabre), dendritic clusters (Reymond and Darbre), calixarenes (Casnati et al.), cyclic peptides (Renaudet et al.) and even nucleic acids (Spinelli and Defrancq). All highlight longer-term applications, especially in applications that may allow probing of interactions in whole organisms, and these are especially elegantly drawn out in the chapter by Penadés et al. that consider particles of many relevant types. Typically syntheses of glycoconjugates adopt one of two strategies. The first strategy is the formation of the glycanaglycone link early, to form, for example, glycosylated building blocks such as glycosides, glycopeptides or glycosylated dendritic wedges, that may then be assembled. While, of course, chemical methods can create glycosidic bonds in a number of ways, the use of biocatalysts can bring with it advantages of selectivity and efficiency; Křen’s chapter highlights this utility well. The second strategy is formation of the link later on in the synthesis once the scaffold for its presentation is in place. Given the instability that may be associated with the link and the requirements for protection that need to be considered in the use of glycosylated building blocks, it is clear why the latter has often seemed the most attractive option. Peri has deftly summarized a broad range of methods for this late stage approach as applied to many useful platform types. Nativi et al. have delineated an emerging area that could allow access to glycomimetics based on the use of glycals in cycloadditions. Together, these chapters give a powerful insight into the elucidation of the mechanism by which sugar-binding takes place, the tools used to probe into it and its consequences. This science has driven and continues to drive the synthesis and technology of glycoconjugates. These are the new tools of the glycobiology trade and I believe only the very start of an era of emerging diagnostics and therapeutics. i Prof. Ben Davis University of Oxford UK
ii PREFACE The interactions between carbohydrates and proteins are involved in major physiological and pathological events. With the recent emergence of glycomics, an increasing number of sophisticated glycosylated structures capable of mimicking the multivalent display of the cell surface glycocalix has been reported. Besides giving precious guidelines on the binding parameters that govern these complex biological processes, synthetic glycoconjugates often revealed considerable interests for diagnostic and therapeutic applications. Our main motivation to edit Synthesis and biological applications of glycoconjugates was to update the major advancements in this field through several chapters written by renowned experts who have largely contributed to the recent progresses. Illustrated with more than 200 colour figures and including literature citations mostly from the last decade, this book covers the recent chemical methods of glycoconjugates and clearly highlights their diverse biological properties. Chapter 1 analyzes the structure of lectins from pathogenic bacteria and gives structure/function relationships that are crucial for the development of high affinity ligands. In Chapter 2 carbohydrate binding by FimH is discussed and modern means for its investigation including photoaffinity labelling are described. Very recent crystallographic work is also documented that provides an explanation for shearenhanced binding of type 1 fimbriated E. coli. Chapter 3 summarizes the most convenient methodologies for the synthesis of glycocalixarenes and describes their impressive aggregation properties and many other biological applications. Chapter 4 illustrates examples of bacterial and human lectins together with bacterial toxins having varied number of carbohydrate recognition domains that necessitated multivalent glycoconjugates. It focuses on glycofullerenes that have been used to describe novel synthetic strategies and possible fit with concomitant lectins. In Chapter 5 the structures of the cholera and E. coli heat-labile toxins are described. The authors also summarize the main strategies that have led to the development of monovalent and multivalent inhibitors of these toxins and they discuss the importance of chelation and protein aggregation as mechanisms of multivalent inhibition. Chapter 6 focuses on the design of high affinity ligands for galectins and provides a better knowledge of the implications of these proteins in biology. Chapter 7 demonstrates that combinatorial chemistry led to the discovery of glycopeptide dendrimers as strong ligands for lectins or drug-delivery systems and shows how the amino acid composition of the dendrimer branches can influence their biological activity. Chapter 8 focuses on the synthesis of a recent class of glycoclusters displayed on a cyclopeptide platform and highlights their promising biological properties, in particular as inhibitors or synthetic vaccines. Chapter 9 shows that the cellular delivery and bioavailability of oligonucleotides can be improved by their conjugation with carbohydrates and also describes the construction of carbohydrate biochips or glycoclusters using these conjugates. Chapter 10 focuses on glycoliposomes and covalentlyfunctionalized glyconanoparticles which make use of the “glyco-code” to address specifically pathogens or pathological-related problems. Chapter 11 focuses on the synthesis of glycoproteins, glycopeptides, glycosylated natural compounds, carbohydrate-functionalized surfaces and nanoparticles using chemoselective glycosylation. In Chapter 12 the recent developments in glycosidase-catalyzed synthesis of unnatural semi-synthetic carbohydrate structures are presented. Chapter 13 reports the synthesis of glycomimetics and glycopeptidomimetics using hetero- Diels Alder reactions between ,’-dioxothiones and glycals. Chapter 14 aims at describing the usual methods to characterize protein-carbohydrate interactions, namely inhibition of hemagglutination assay, enzyme-linked lectin assays, isothermal titration calorimetry, surface plasmon resonance and the more recent atomic force microscopy. We believe that this Ebook will be of particular interest to a large community of graduate students, researchers and professionals in academia or industry involved in Glycoscience. We would like to express our sincerest gratitude to all of the authors who accepted to contribute to this exciting project, by sharing their strong experiences and knowledge in this research area. Olivier Renaudet Nicolas Spinelli University of Grenoble France
Page 2 and 3: Synthesis and Biological Applicatio
Page 4 and 5: CONTENTS Foreword i Preface ii List
Page 8 and 9: List of Contributors Didier Boturyn
Page 12 and 13: Bacterial Lectins and Adhesins Synt
Page 14 and 15: Ligands for FimH Synthesis and Biol
Page 16 and 17: 36 Synthesis and Biological Applica
Page 20 and 21: Solving Promiscuous Protein Carbohy
Page 26 and 27: Monovalent and Multivalent Glycocon
Page 28 and 29: 116 Synthesis and Biological Applic
Page 36 and 37: Oligonucleotide-Carbohydrate Conjug
Page 38 and 39: Glycoliposomes and Metallic Glycona
Page 42 and 43: Chemoselective Glycosylation Techni
Page 44 and 45: Glycosidases in Synthesis of Glycom
Page 52 and 53: A Synthesis and Biological Applicat
Page 54: Index Synthesis and Biological Appl

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