List of contributors xiii
Preface xvii
Section I New Developments in Peptide Chemistry 1
1 Chemical Peptide Ligations 3
Yihui Cao and Xuechen Li
1.1 Introduction 3
1.2 Ligation Driven by Trans-esterification 4
1.3 Ligation Driven by Imine Capture 8
1.4 Ligation Initiated by Hydroxylamine 10
1.5 Ligation in Protein Synthesis 12
1.6 Ligations in Drug Development 17
1.7 Summary and Outlook 21
2 Protein and Peptide Ligation Using Peptide Ligases 29
Anna Koijen and Leendert J. van den Bos
2.1 Introduction 29
2.2 Peptide Ligases Mechanism of Action 32
2.3 Sortase 33
2.4 Peptide Asparaginyl Ligases 38
2.5 Subtilisin-derived Peptide Ligases 41
2.6 Trypsiligase 44
2.7 Conclusion 46
3 Modern Methods for Late-stage Peptide Modification 55
Yuxuan Ding and Zachary T. Ball
3.1 Introduction 55
3.2 Methionine 57
3.3 Aspartate and Glutamate 59
3.4 Arginine 61
3.5 Tryptophan 62
3.6 Functionalization of sp2 C-H Bonds: Tyr, Phe, and His 66
3.7 Functionalization of sp3 C-H Bonds 71
3.8 Other X-H Functionalizations 73
3.9 Conclusion 74
Section II Peptide Drug Hit Identification 87
4 Generating Phage Libraries Bearing Unnatural Pharmacophores 89
Christin Kossmann, Arunika Ekanayake and Ratmir Derda
4.1 Introduction 89
4.2 Biotin Capture Assay to Detect Chemical Modification of Phage Libraries 93
4.3 N-terminal Oxidation and Functionalization to Incorporate Unnatural Fragments 106
4.4 Macrocyclization of Phage-displayed Peptides Bearing Cysteines 110
4.5 Macrocyclization and Installation of Warheads in Phage-displayed Libraries 114
4.6 Outlook 120
5 Computational Peptide Design for Diverse Structures and Functions 127
Stephen Rettie, David Juergens and Gaurav Bhardwaj
5.1 The Various Types of Peptides 128
5.2 In Silico Peptide Design: From Physics-based Methods to DL 129
5.3 Physics-based Methods 130
5.4 DL Methods for Peptide Design 136
5.5 Optimizing for Membrane Permeability and Stability 140
5.6 Remaining Challenges 141
5.7 Conclusion 143
Section III Peptide Drug Lead Generation and Optimization 151
6 Peptide Discovery: Lead Generation 153
Yvonne Angell, Wendy Hartsock, Hans Melo and Timothy M. Reichart
6.1 Introduction 153
6.2 Approved Drugs Discovered Through Phage Display 174
6.3 Approved Drugs Discovered Through mRNA Display 177
6.4 A Successful Example 185
6.5 Conclusion 188
7 A Survey and Guide to the Development of Fatty Acid-derivatized Peptide Therapeutics 203
Michael T. Jacobsen, Christian Poulsen, Katharina L. Kopp, J¸rgen Olsen and Nick Cox
7.1 Introduction 203
7.2 Basics of Fatty Acid Derivatization of Peptides 204
7.3 Evolution of GLP-1-based Incretins into Stable, Long-acting Therapeutics 205
7.4 Diverse Mechanisms of Fatty Acid Derivatization to Extend Insulin Half-life 210
7.5 Development of a Stable, Fatty Acid-derivatized Amylin Analog 214
7.6 Stabilization and Fatty Acid Derivatization of Peptide YY (PYY) 217
7.7 Guidance for Advancing Fatty Acid-derivatized Peptides 222
7.8 Concluding Remarks 242
Section IV Peptide Drug Case Studies 269
8 Insulin in Its Second Century: History, Evolution, and Aspirations 271
John P. Mayer, Kishore Thalluri, Ethan Mickelson, Michael H.B. Stowell and Richard D. DiMarchi
8.1 Introduction 271
8.2 The Evolution of Insulin Therapy 272
8.3 Structure 278
8.4 Synthesis 280
8.5 Aspirational Aims 286
8.6 Concluding Thoughts 290
9 Incretins and Development of Incretin-based Therapeutics 305
Nan Zheng, Xiao-xuan Su, Shengping Zhang and Weijun Shen
9.1 Introduction 305
9.2 Development of Novel GLP-1 and GIP-based Therapeutics 309
9.3 Development of Multi-receptor Agonists Targeting Incretin and Other Hormonal Receptors 315
9.4 Summary and Perspective 329
10 Peptide-based Therapeutics for Inflammatory and Autoimmune Diseases 339
Sunay V. Chankeshwara, Werngard Czechtizky and Wu Su
10.1 Introduction 339
10.2 Literature Search and Methods 341
10.3 Representative Anti-inflammatory Peptides in Clinical Trials 342
10.4 Summary and Discussion 351
11 Radioligand as a Unique Rising Modality for Cancer Diagnosis and Treatment 359
Ming-Jin Jheng, Xiaozhu Wang, Pengyun Li and Fa Liu
11.1 Radioligand Introduction 359
11.2 Radionuclides and Chelators Developed for Medical Imaging and Cancer Treatment 361
11.3 Notable Radioligands Developed for Cancer Diagnosis and Treatment 364
11.4 Emerging Targets 371
11.5 Emerging Binder Modalities as Radioligand Vector 379
11.6 Perspectives: Promises and Challenges 384
12 Peptide-small Molecule Drug Conjugates for Cancer, Metabolic Diseases, and Beyond 401
Rongjun He, Sumeet Singh and Adam Mezo
12.1 Introduction 401
12.2 Peptide-drug Conjugates for Cancer 402
12.3 Peptide-drug Conjugates for Metabolic Diseases 409
12.4 Peptide-drug Conjugates for Other Diseases 415
12.5 Challenges in Peptide-drug Conjugate Design 415
12.6 Summary 416
13 Emerging Landscape of Therapeutic Oligonucleotide Delivery by Cell-penetrating Peptide 425
Xiang Li, Xiulong Shen, Ashweta Sahni and Ziqing Qian
13.1 Introduction 425
13.2 Cell-penetrating Peptides 426
13.3 Applications of CPPs for the Delivery of Therapeutic Oligonucleotides 433
13.4 Future Perspectives and Summary 447
Section V Peptide CMC and Regulatory 469
14 Peptides Chemistry, Manufacturing, and Controls 471
Jack Xu
14.1 Introduction 471
14.2 CMC Information and Format for DS 472
14.3 CMC Information and Format for DP 477
14.4 Synthetic Peptide CMC Development 483
14.5 Conclusions 504
Index 509
