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<p>Foreword xv</p> <p>Acknowledgments xvii</p> <p><b>1 Antibacterial Carbohydrate Vaccines 1<br /> </b><i>Federica Compostella, Laura Morelli, and Luigi Lay</i></p> <p>1.1 Introduction 1</p> <p>1.1.1 A Brief History of Vaccines 2</p> <p>1.2 Carbohydrate-Based Vaccines 5</p> <p>1.2.1 Mechanism of the Immune Response to Carbohydrate-Based Vaccines 12</p> <p>1.3 Components of Glycoconjugate Vaccines 15</p> <p>1.3.1 The Carbohydrate Antigen 16</p> <p>1.3.2 Linkers for Carbohydrate–Protein Conjugation 19</p> <p>1.3.3 The Carrier Protein 22</p> <p>1.3.4 The Adjuvant 24</p> <p>1.4 Technologies Employed for Production of Glycoconjugate Vaccines 25</p> <p>1.4.1 Traditional Glycoconjugates 26</p> <p>1.4.2 Glycoconjugates Based on Synthetic Carbohydrate Antigens 28</p> <p>1.4.2.1 Site-Selective Protein Conjugation 29</p> <p>1.4.3 Enzymatic and ChemoEnzymatic Approach 30</p> <p>1.4.4 Bioengineered Glycoconjugates 31</p> <p>1.4.5 Nanotechnology-Based Glycoconjugate Vaccines 33</p> <p>1.4.5.1 Outer Membrane Vesicles (OMVs) and Generalized Modules for Membrane Antigens (GMMA) 33</p> <p>1.4.5.2 Gold Nanoparticles, Liposomes, and Virus-Like Particles 34</p> <p>1.4.6 Nonprotein-Based Glycoconjugates 36</p> <p>1.4.7 Noncovalent Vaccines 36</p> <p>1.5 Conclusion 37</p> <p>Acknowledgments 38</p> <p>References 39</p> <p><b>2 Antifungal Glycoconjugate Vaccines 57<br /> </b><i>Linda del Bino, Maria R. Romano, and Roberto Adamo</i></p> <p>2.1 Human Fungal Infections 57</p> <p>2.2 Immunity Against Fungal Pathogens 59</p> <p>2.3 Carbohydrate Antigens in Fungal Cell Wall 60</p> <p>2.4 Glycoconjugate Vaccines Against Candida albicans/Candida auris 61</p> <p>2.5 Glycoconjugate Vaccines Against Cryptococcus neoformans 64</p> <p>2.6 Glycoconjugate Vaccines Against Aspergillus fumigatus 66</p> <p>2.7 Universal Fungal Polysaccharide Antigens 68</p> <p>2.8 Conclusions and Future Prospects 68</p> <p>References 69</p> <p><b>3 Carbohydrate-Based Antiviral Vaccines 73<br /> </b><i>Adrián Plata and Alberto Fernández-Tejada</i></p> <p>3.1 Introduction 73</p> <p>3.2 Human Immunodeficiency Virus 74</p> <p>3.2.1 Vaccine Constructs Derived from gp120 High-Mannose N-Glycan Cluster 75</p> <p>3.2.1.1 Surface Oligomannose Cluster-Targeting bnAb: 2G12 Antibody 75</p> <p>3.2.1.2 Synthesis and Immunological Evaluation of 2G12 Epitope Mimics 76</p> <p>3.2.2 Vaccine Constructs Derived from gp120 First and Second Variable Loops (V1V2) 81</p> <p>3.2.2.1 V1V2-Targeting bnAbs 81</p> <p>3.2.2.2 Synthetic V1V2 N-Glycopeptide Antigens as bnAb Epitope Mimics 81</p> <p>3.2.3 Vaccine Constructs Derived from gp120 Third Variable Loops (V3) 83</p> <p>3.2.3.1 V3-Targeting bnAbs 83</p> <p>3.2.3.2 Synthetic Glycoconjugates and N-glycopeptides as V3-Directed bnAb Epitope Mimics 83</p> <p>3.2.3.3 Synthetic V3 Glycopeptides as bnAb Epitope Mimics 83</p> <p>3.3 Influenza A Virus 85</p> <p>3.3.1 Vaccine Constructs Based on Hemagglutinin (HA) 86</p> <p>3.3.1.1 Hyperglycosylated HA Vaccines 87</p> <p>3.3.1.2 α-Gal-Based Vaccine Constructs 87</p> <p>3.3.2 Vaccine Constructs Based on Neuraminidase (NA) 88</p> <p>3.3.3 Acetalated Dextran as Adjuvant Carrier 89</p> <p>3.3.4 Multivalent Constructs as Anti-Influenza Inhibitors 89</p> <p>3.4 Hepatitis C Virus 90</p> <p>3.5 Ebola Virus 91</p> <p>3.5.1 Glycoprotein-Based Vaccines 92</p> <p>3.5.2 Monoclonal Antibodies and Carbohydrate Antiviral Agents as Therapeutics 92</p> <p>3.6 SARS-CoV-2 Virus 94</p> <p>3.6.1 Prospective Vaccine Constructs Based on α-Gal Epitope 94</p> <p>3.6.2 RBD-Based Constructs for Vaccine Development 95</p> <p>3.6.3 Saponins as Carbohydrate-Based Adjuvant Candidates for COVID- 19 Vaccines 95</p> <p>3.7 Conclusions and Outlook 96</p> <p>Acknowledgments 96</p> <p>References 97</p> <p><b>4 Bacterial Glycolipid Lipid As and Their Potential as Adjuvants 111<br /> </b><i>Atsushi Shimoyama and Koichi Fukase</i></p> <p>4.1 Introduction 111</p> <p>4.2 Bacterial Glycolipid Lipid A: an Innate Immune Stimulant 113</p> <p>4.3 Vaccines Containing Natural LPS as Adjuvants 117</p> <p>4.3.1 Cholera Vaccines 117</p> <p>4.3.2 Salmonella enterica Serovar Typhi Vaccines 117</p> <p>4.3.3 Other Vaccines 118</p> <p>4.4 LPS and Lipid A in the Environment or Fermented Foods as Adjuvants 118</p> <p>4.5 Synthetic and Semisynthetic Lipid As as Adjuvants 120</p> <p>4.6 Developing Novel Lipid A Adjuvants 121</p> <p>4.6.1 Parasitic Bacterial Lipid As 121</p> <p>4.7 Symbiotic Bacterial Lipid As 123</p> <p>4.8 Lipid A-Based Self-Adjuvanting Vaccines 125</p> <p>4.9 Conclusions 127</p> <p>References 127</p> <p><b>5 Antiadhesive Carbohydrates and Glycomimetics 131<br /> </b><i>Jonathan Cramer, Lijuan Pang, and Beat Ernst</i></p> <p>5.1 Introduction 131</p> <p>5.1.1 Carbohydrate–Protein Interactions in Viral Adhesion to Host Cells 131</p> <p>5.1.2 Bacterial Adhesins and Antiadhesion Therapy 132</p> <p>5.1.3 Selected Examples 133</p> <p>5.2 DC-SIGN-Mediated Viral Adhesion and Entry into Myeloid Cells 133</p> <p>5.2.1 Introduction 133</p> <p>5.2.2 DC-SIGN Ligands Employing Natural Carbohydrate Epitopes 136</p> <p>5.2.2.1 Dendrimers 137</p> <p>5.2.2.2 Nanoparticles 137</p> <p>5.2.2.3 Polymers 138</p> <p>5.2.2.4 Other Multivalent Scaffolds 138</p> <p>5.2.3 DC-SIGN Ligands Employing Carbohydrate Derivatives or Glycomimetics 139</p> <p>5.2.4 Conclusion and Perspectives 141</p> <p>5.3 The Bacterial Adhesin FimH 143</p> <p>5.3.1 UTIs and FimH 143</p> <p>5.3.2 FimH CRD 143</p> <p>5.3.3 FimH Antagonists 145</p> <p>5.3.4 Conclusion and Perspectives 147</p> <p>5.4 Pseudomonas aeruginosa Virulence Factors (PA-IL and PA-IIL) 148</p> <p>5.4.1 Introduction 148</p> <p>5.4.2 Mono- and Oligovalent Glycomimetic PL-Ligands 149</p> <p>5.4.3 Conclusions and Perspectives 152</p> <p>5.5 General Aspects 152</p> <p>References 153</p> <p><b>6 Targeting Carbohydrates in Cancer – Analytical and Biotechnological Tools 161<br /> </b><i>Henrique O. Duarte, Joana Gomes, and Celso A. Reis</i></p> <p>6.1 Aberrant Protein Glycosylation in Cancer 161</p> <p>6.2 Detection and Mapping of Carbohydrate-Based Antigens in Human Neoplastic Tissues 164</p> <p>6.3 Imaging Mass Spectrometry 164</p> <p>6.4 In Situ Proximity Ligation Assay 166</p> <p>6.5 Glycan Microarrays 169</p> <p>6.6 Glycoengineered In Vitro, In Vivo, and Ex Vivo Models 171</p> <p>6.7 Structural Elucidation of Glycoconjugates: Glycomic and Glycoproteomic Strategies 176</p> <p>6.8 Concluding Remarks 182</p> <p>List of Abbreviations 183</p> <p>References 185</p> <p><b>7 Carbohydrate-Specific Monoclonal Antibody Therapeutics 201<br /> </b><i>Matthew Lohman, Hannah Rowe, and Peter R. Andreana</i></p> <p>7.1 Introduction 201</p> <p>7.2 Types of Monoclonal Antibodies 202</p> <p>7.2.1 IgG Antibodies 202</p> <p>7.2.2 IgM Antibodies 203</p> <p>7.2.3 ScFv and Fab Fragments 203</p> <p>7.3 Humanization of Monoclonal Antibodies 204</p> <p>7.3.1 CDR Grafting 204</p> <p>7.3.2 Transgenic Animals 204</p> <p>7.4 Breakthrough Research 205</p> <p>7.5 mAbs from Preclinical to Clinical Studies 206</p> <p>7.6 Globo Series 206</p> <p>7.6.1 Blood Group 206</p> <p>7.6.2 Mucin-Attached Glycans 207</p> <p>7.7 New Treatment Options for Neuroblastoma 207</p> <p>7.7.1 History of Unituxin 208</p> <p>7.7.2 What is Unituxin? 209</p> <p>7.7.3 Challenges with Unituxin 211</p> <p>7.7.4 mAbs Binding to Neuroblastoma 211</p> <p>7.7.5 Chimeric and Humanized Anti-GD2 Antibodies 212</p> <p>7.7.6 Naxitamab as a Potential Alternative for High-Risk Patients 212</p> <p>7.7.7 Chimeric Antigen Receptors (CARs) Targeting GD2 213</p> <p>7.8 Summary 214</p> <p>List of Abbreviations 215</p> <p>References 216</p> <p><b>8 Carbohydrates in Tissue Engineering 223<br /> </b><i>Laura Russo and Francesco Nicotra</i></p> <p>8.1 Introduction 223</p> <p>8.2 Biomaterials and Medical Devices: Natural and Synthetic Strategies 224</p> <p>8.2.1 Carbohydrates as Building Blocks for Medical Device Formulation 224</p> <p>8.2.1.1 Human Polysaccharides: Glycosaminoglycans (GAGs) and Proteoglycans (PGs) 225</p> <p>8.2.1.2 Polysaccharides from Plants, Algae, Animal, and Microbial Fermentation 228</p> <p>8.2.2 Carbohydrates as Signaling Molecules: Opportunities in Tissue Engineering and Regenerative Medicine 233</p> <p>8.3 Carbohydrates in Animal-Derived Medical Devices: Friends or Foes? 234</p> <p>8.4 Glycoengineering Application to Regenerative Medicine 235</p> <p>8.5 Future Opportunities and Major Challenges 237</p> <p>Conflict of Interest 237</p> <p>References 237</p> <p><b>9 Carbohydrate-Based Therapeutics for Lysosomal Storage Disorders 245<br /> </b><i>Camilla Matassini, Francesca Clemente, and Francesca Cardona</i></p> <p>9.1 An Introduction to Lysosomal Storage Disorders (LSDs) 245</p> <p>9.2 Available Treatments for LSDs: The Role of Carbohydrate-Based Therapeutics 248</p> <p>9.2.1 Enzyme Replacement Therapy (ERT) 250</p> <p>9.2.2 Substrate Reduction Therapy (SRT) 251</p> <p>9.2.3 Pharmacological Chaperone Therapy (PCT) 252</p> <p>9.2.4 Combined ERT/PC Therapy 254</p> <p>9.3 Mucopolysaccharidoses 254</p> <p>9.4 Sphingolipidoses 258</p> <p>9.4.1 Fabry Disease 258</p> <p>9.4.2 Gaucher Disease 262</p> <p>9.4.3 Niemann–Pick 267</p> <p>9.4.4 GM1 Gangliosidosis and Morquio B (β-Gal) 268</p> <p>9.4.5 GM2 Gangliosidosis (β-Hexosaminidase) 272</p> <p>9.4.6 Krabbe 275</p> <p>9.5 Glycogen Storage Disorders 275</p> <p>9.5.1 Pompe Disease 275</p> <p>9.6 Glycoproteinoses 277</p> <p>9.6.1 Fucosidosis 277</p> <p>9.6.2 α-Mannosidosis 279</p> <p>9.7 Conclusions 279</p> <p>Acknowledgments 282</p> <p>Abbreviations and Acronyms 283</p> <p>References 284</p> <p><b>10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease 293<br /> </b><i>Ana M. Matos, João Barros, and Amélia P. Rauter</i></p> <p>10.1 Introduction 293</p> <p>10.2 O-GlcNAc Transferase (OGT) and O-GlcNAc Hydrolase (OGA) in Neurodegeneration 295</p> <p>10.2.1 O-GlcNAc Cycling as a Therapeutic Target Against Alzheimer’s Amyloid Plaques and Neurofibrillary Tangles 296</p> <p>10.2.2 OGA Inhibitors 299</p> <p>10.2.2.1 PUGNAc 301</p> <p>10.2.2.2 GlcNAcstatins 305</p> <p>10.2.2.3 Thiazoline Inhibitors 311</p> <p>10.3 GalNAc in Neurodegeneration 322</p> <p>10.4 Chitosan and Derivatives in AD Brain 324</p> <p>10.5 Cholinesterase Inhibitors 325</p> <p>10.6 Fyn Kinase Inhibitors 330</p> <p>10.7 Amyloid Protein–Protein Interaction Inhibitors 334</p> <p>10.8 Inhibitors of Aβo and/or Oxidative Stress-Induced Neurotoxicity 338</p> <p>10.9 Carbohydrate–Protein Interactions as Potential Therapeutic Targets Against AD 341</p> <p>10.9.1 Lipid-Raft Gangliosides as Membrane Accumulation Sites for Toxic Aβ Aggregates 341</p> <p>10.9.2 The Role of Microglial Cells in Aβ Brain Clearance 342</p> <p>10.10 Conclusion 343</p> <p>List of Abbreviations 344</p> <p>Acknowledgments 347</p> <p>References 347</p> <p><b>11 Carbohydrate-Based Antithrombotics 353<br /> </b><i>Antonella Bisio, Marco Guerrini, and Annamaria Naggi</i></p> <p>11.1 Introduction 353</p> <p>11.2 Antithrombotic Drugs 354</p> <p>11.3 Heparin 354</p> <p>11.4 Mechanism of Interaction with Coagulation Factors 357</p> <p>11.4.1 Antithrombin-Mediated Activity 357</p> <p>11.4.2 Heparin Cofactor II Mediated Activity 360</p> <p>11.4.3 Additional Factors 360</p> <p>11.4.4 Adverse Effects of Heparin 360</p> <p>11.4.4.1 Heparin-Induced Thrombocytopenia 361</p> <p>11.4.4.2 Osteoporosis 361</p> <p>11.5 Low Molecular Weight Heparins 361</p> <p>11.5.1 Ultralow Molecular Weight Heparins 363</p> <p>11.6 Drugs Based on Natural GAG Mixtures 363</p> <p>11.6.1 The Role of Dermatan Sulfate 364</p> <p>11.6.2 Sulodexide 364</p> <p>11.6.3 Danaparoid 365</p> <p>11.6.4 Mesoglycan 365</p> <p>11.7 Defibrotide 366</p> <p>11.8 Pentosan Polysulfate 367</p> <p>11.9 Fondaparinux and Related Synthetic Oligosaccharides 367</p> <p>11.10 Chemoenzymatic Synthesis of Oligosaccharides 369</p> <p>11.11 Conclusions and Perspectives 369</p> <p>Acknowledgment 369</p> <p>References 370</p> <p>Index 381 </p>

<p><i><b>Roberto Adamo </b>joined GSK (formerly Novartis Vaccines) in 2007 where he was later appointed as Head of the Carbohydrate Chemistry Laboratory, and Leader of the Conjugation & Synthesis Platform. He is currently Project Leader at GSK, Italy.</i></p> <p><i><b>Luigi Lay </b>is Full Professor at the Department of Chemistry of the University of Milan, Italy. His research focuses on carbohydrate chemistry and the use of synthetic glycans to investigate their biological properties.</i></p>

<p><b>Comprehensive resource summarizing opportunities and latest progress in design methodologies for carbohydrate-based therapeutics through a disease-oriented approach</b> <p><i>Carbohydrate-Based Therapeutics </i>covers current progress and explores new frontiers in carbohydrate-based therapeutic applications, utilizing a unique approach by providing a detailed background of diseases coupled with <p>subsequent carbohydrate-based therapies. The link between chemistry and design of novel carbohydrate-based medicines is highlighted and a broad overview of all the potential applications of carbohydrates is given. <p>Emphasis is laid on concepts used for carbohydrate drug design, structure– activity relationship, and impact on health and diseases. The text also discusses newer topics like nanoparticles, material science, and tissue generation. <p><i>Carbohydrate-Based Therapeutics </i>includes information on: <ul><li>Antimicrobial carbohydrate-based therapies, covering antibacterial and antiviral vaccines, antifungal therapies, anti-influenza therapeutics, and antiadhesive carbohydrates and glycomimetics</li> <li>Anti-cancer carbohydrate-based therapies, covering cancer vaccines and immunotherapy, and carbohydrate tools in cancer biology</li> <li>Carbohydrate-based therapies in metabolic, neuronal, and immune disorders, covering carbohydrate-based therapeutics for lysosomal disorders and neurodegenerative diseases</li> <li>New frontiers in carbohydrate-based therapies, covering carbohydrates for tissue engineering, antiangiogenic and regenerative medicine</li></ul> <p>Providing comprehensive coverage of foundational knowledge on the subject in a unique and highly accessible format while also exploring the state of the art in the field’s applications, <i>Carbohydrate-Based Therapeutics </i>is an essential resource for medicinal, pharmaceutical, and organic chemists, chemists in industry, biochemists, and biotechnologists.

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