Peptide Chemistry and Drug Design

Ben Dunn is a Distinguished Professor in the Department of Biochemistry and Molecular Biology at the University of Florida. Dr. Dunn has served on many NIH review panels and is on the editorial board of Current Protocols in Protein Science. He is an author on 200 peer-reviewed publications and 4 books. Prof. Dunn has been a councillor, president-elect, president, and now past-president of the American Peptide Society.

• Preface xiList of Contributors xv1 Peptide Therapeutics 1Nader Fotouhi1.1 History of Peptides as Drugs 11.2 Factors Limiting the Use of Peptides in the Clinic 21.3 Advances That Have Stimulated the Use of Peptides as Drugs 31.4 Development of Peptide Libraries 41.5 Modification of Peptides to Promote Stability and Cell Entry 61.6 Targeting Peptides to Specific Cells 71.7 Formulations to Improve Properties 7References 82 Methods for the Peptide Synthesis and Analysis 11Judit Tulla-Puche, Ayman El-Faham, Athanassios S. Galanis, Eliandre de Oliveira, Aikaterini A. Zompra, and Fernando Albericio2.1 Introduction 112.2 Solid Supports 132.3 Linkers 152.4 Protecting Groups 172.4.1 The Special Case of Cysteine 182.5 Methods for Peptide Bond Formation 202.5.1 Peptide-Bond Formation from Carbodiimide-Mediated Reactions 202.5.2 Peptide-Bond Formation from Preformed Symmetric Anhydrides 222.5.3 Peptide-Bond Formation from Acid Halides 232.5.4 Peptide-Bond Formation from Phosphonium Salt-Mediated Reactions 232.5.5 Peptide-Bond Formation from Aminium/Uronium Salt-Mediated Reactions 242.6 Solid-Phase Stepwise Synthesis 262.6.1 Long Peptides 272.7 Synthesis in Solution 292.7.1 NProtection of the N-Terminal Amino Acid Derivative or Fragment 302.7.2 Carboxy-Group Protection of the C-terminal Amino-Acid Derivative or Fragment 312.7.3 Peptide Bond Formation 342.8 Hybrid Synthesis–Combination of Solid and Solution Synthesis 342.8.1 Classical Segment Condensation 352.8.2 Native Chemical Ligation 362.9 Cyclic Peptides 372.10 Depsipeptides 382.11 Separation and Purification of Peptides 402.11.1 Gel-Filtration Chromatography 412.11.2 Ion-Exchange Chromatography 412.11.3 Reverse-Phase High Performance Liquid Chromatography 422.12 Characterization of Peptides Through Mass Spectrometry 432.12.1 Ionization Source 442.12.2 Mass Analysers 452.12.3 Peptide Fragmentation 492.12.4 Quantification by MS 512.13 Conclusions 52Acknowledgments 53Abbreviations 53References 563 Peptide Design Strategies for G-Protein Coupled Receptors (GPCRs) 75Anamika Singh and Carrie Haskell-Luevano3.1 Introduction 753.2 Classification of GPCRs 763.3 Catalog of Peptide-Activated G-Protein Coupled Receptors 773.4 Structure of GPCRs: Common Features 773.4.1 Crystal Structures 773.5 GPCR Activation 933.5.1 Ligand (Peptide) Binding and Receptor Activation 943.5.2 Common Structural Changes among GPCRs 953.5.3 G-Protein Coupled Intracellular Signaling Pathways 953.6 Structure and Function of Peptide Hormones 983.7 Design Approaches for GPCR Selective Peptide Ligands 983.7.1 Structure–Activity Relationship (SAR) Studies 993.7.2 Chimeric Peptide Analogs 1033.7.3 Combinatorial Libraries 1033.7.4 Three-Dimensional (3D) GPCR Homology Molecular Modeling 1043.8 Conclusions 105Acknowledgments 105References 1054 Peptide-Based Inhibitors of Enzymes 113Anna Knapinska, Sabrina Amar, Trista K. Robichaud, and Gregg B. Fields4.1 Introduction 1134.2 Angiotensin-Converting Enzyme and Neprilysin/Neutral Endopeptidase 1144.3 Peptide Inhibitors of the HIV-1 Viral Life Cycle 1174.4 Matrix Metalloproteinases 1184.5 Antrax Lethal Factor Inhibition by Defensins 1254.6 Kinases 1274.7 Glycosyltransferases (Oligosaccharyltransferases) 1314.8 Telomerase Inhibitors 1344.9 Tyrosinase 1384.10 Peptidyl-Prolyl Isomerase 1404.11 Histone Modifying Enzymes 1434.11.1 Histone Deacetylase 1444.11.2 Histone Methyl-Transferase 1454.12 Putting it all Together: Peptide Inhibitor Applications in Skin Care 1464.13 Strategies for the Discovery of Novel Peptide Inhibitors 147Acknowledgments 148References 1485 Discovery of Peptide Drugs as Enzyme Inhibitors and Activators 157Jeffrey-Tri Nguyen and Yoshiaki Kiso5.1 Introduction 1575.1.1 Peptide Residue Nomenclature 1585.1.2 Common Methods of Drug Design 1595.1.3 Phases of Drug Development 1635.2 Enzyme Types That Process Peptides 1645.2.1 Enzymes as Chemicals in Consumer and Medical Products 1645.2.2 Nonspecific Enzyme Inhibitors 1665.3 Amino Acid Drugs 1665.3.1 Thyroid Hormones 1665.3.2 An Ornithine Decarboxylase Inhibitor 1675.3.3 Catecholamines 1685.4 Serine Proteases and Blood Clotting 1695.4.1 Blood Coagulating Agents 1705.4.2 Enzymes as Blood Anticoagulants 1715.4.3 Direct Thrombin Inhibitors as Blood Anticoagulants 1715.5 Diabetes Mellitus 1745.5.1 Peptide Hormones and Blood Glucose Regulation 1745.5.2 Glucagon-Like Peptide-1 and Analogs 1755.5.3 Dipeptidyl Peptidase-4 Inhibitors 1765.6 Renin–Angiotensin–Aldosterone System 1785.6.1 ACE Inhibitors 1785.6.2 Renin Inhibitors 1805.7 Penicillin and Cephalosporin Antibiotics 1835.8 HIV Protease 1845.8.1 HIV-Specific Protease Inhibitors 1855.9 Peptide Drugs Under Development 1885.9.1 Cathepsins 1885.9.2 Cysteine Proteases 1895.9.3 Secretases in Alzheimer’s Disease 1895.9.4 Trypsin-Like Serine Proteases 1905.9.5 Zinc Metalloproteases 1905.9.6 Non-mammalian Proteases 1915.10 Discussion 192Acknowledgments 193References 1936 Discovery of Peptide Drugs from Natural Sources 203Sónia T. Henriques and David J. Craik6.1 Introduction 2036.2 Peptides are Involved in the Host Defense Mechanism of Living Organisms 2066.2.1 Cationic AMPs from Eukaryotes Peptides that Target the Membrane 2076.2.2 Peptides and the Host Defense in Bacteria – Bacteriocins 2116.2.3 Cyclotides Ultra-Stable Peptides that are Part of Plant Defense Mechanism 2166.3 Animal Venoms a Rich Source of Peptides with Therapeutic Potential 2196.3.1 Conotoxins a Naturally Occurring Combinatorial Peptide Library 2196.4 Optimization of Peptides for Drug Development 2246.4.1 Chemical Modifications to Improve Activity 2246.5 Conclusions 227Acknowledgments 227References 2277 Modification of Peptides to Limit Metabolism 247Isuru R. Kumarasinghe and Victor J. Hruby7.1 Introduction 2477.2 Introduction of Unnatural Amino Acids 2487.3 Cyclization of Linear Peptides to Improve Stability Toward Blood and Brain Protease Degradation 2497.4 Introduction of D-Amino Acids into Peptides Improves Stability Toward Blood and Brain Protease Degradation 2537.5 Introduction of β-Amino Acids Increases the Stability Toward Blood and Brain Protease Degradation 2547.6 Introduction of Peptide Bond Isosteres 2557.7 Introduction of a N-Methylation of the Amide Bond of Peptides Can Improve the Stability Toward Blood and Brain Protease Degradation 2587.8 Use of Unnatural Amino Acids – Use of Topographically Constrained Amino Acid 2607.9 Using Glycosylated Amino Acids to Increase the Resistance of the Proteolytic Degradation 2617.10 Creation of Peptides as Multiple Antigen Peptide (MAP) Dendrimeric Forms Increases the Stability Toward Blood and Brain Protease Degradation 2627.11 Halogenations of Aromatic Residues in Peptides Can Reduce the Enzymatic Recognition Required for Peptide Hydrolysis 2637.12 Concluding Discussion 264References 2658 Delivery of Peptide Drugs 271Jeffrey-Tri Nguyen and Yoshiaki Kiso8.1 Introduction 2718.2 Lipinski’s Rule of Five 2718.2.1 Molecular Size 2728.2.2 Lipophilicity 2748.2.3 Chemical Stability 2788.2.4 Routes of Administration 2828.3 Approaches to Delivering Peptide Drugs 2828.3.1 Enzyme Inhibitors 2838.3.2 Permeation Enhancers 2848.3.3 Delivery of Peptide Drugs across the Blood–Brain Barrier 2868.4 Parenteral Peptide Drugs 2908.5 Topical Peptide Drugs for Local Effects 2948.5.1 Cosmeceutical Peptides 2948.6 Intranasal Peptide Drug Delivery 2958.7 Enteral Peptide Drugs 2978.8 Different Routes of Administration for Insulin 2998.9 Discussion 300Acknowledgments 301References 301Index 311