Preface xi
Abbreviations xiii

PART I Chemistry Toolbox 1

1. Overview of Peptidomimetic Concepts and Design 3
1.1 Introduction 3
1.2 Definition and Classification 5
1.3 In Silico Tools for Peptidomimetic Design 7
1.4 Overview of Synthetic Approaches Toward Peptidomimetics 11
1.5 Amino Acid and Peptide Bioisosterism 14
1.6 Local Modifications: The Tethering Approach 18
1.7 Heterocyclic Peptidomimetics 19
1.8 Global Restrictions 23
1.9 Therapeutic and Diagnostic Applications of Peptidomimetics 29
1.10 Conclusion 33

2. Multicomponent Reactions Toward Peptidomimetics 41
2.1 Introduction 41
2.2 Isocyanide-Based MCRs 43
2.3 Imine-Based MCRs 49
2.4 Tandem MCRs 54
2.5 Combination of MCRs with Other Processes 55
2.6 Biological Applications of MCRs in Peptidomimetic Design 56
2.7 Conclusion 59

3. Non-Coded Amino Acids: Cyclic Scaffolds and C—H Functionalization 65
3.1 Introduction 65
3.2 Cyclic Amino Acids 65
3.3 Principles of C—H Functionalization 77
3.4 C—H Functionalization of Amino Acids 83
3.5 Conclusion 90

4. Late-Stage Functionalization of Peptides 97
4.1 Introduction 97
4.2 Classification of Late-Stage Functionalization of Peptides 100
4.3 Backbone Modification 103
4.4 Side-Chain Functionalization 109
4.5 Conclusion 117

PART II Peptidomimetic Compounds 123

5. Macrocyclic Peptides and Peptidomimetics 125
5.1 Introduction 125
5.2 Classification of Macrocyclic Peptides 127
5.3 Peptide Macrocyclization Chemistry 127
5.4 Case Studies of Macrocyclic Peptides in Drug Discovery Applications 147
5.5 Conclusion 153

6. Stapled Peptides 159
6.1 Introduction 159
6.2 Strategic Approaches for Peptide-Stapling Design 161
6.3 Chemical Methods for Peptide Stapling 164
6.4 Therapeutic Applications 175
6.5 Conclusion 179

7. Advances in Peptidomimetic Foldamers 187
7.1 Introduction 187
7.2 Secondary-Structure Mimetics 189
7.3 Peptidomimetic Foldamers 190
7.4 Application of Secondary-Structure Mimetic Foldamers in Drug Discovery 198
7.5 Conclusion 202

PART III Applications and Case Studies in Drug Discovery 209

8. Peptidomimetic SARS-CoV-2 Main Protease Inhibitors 211
8.1 Introduction 211
8.2 Structure and Replication Cycle of SARS-CoV-2 212
8.3 Approved Vaccines and Antiviral Treatments 214
8.4 Therapeutic Targets and Approaches 215
8.5 Structure and Function of the Main Protease (Mpro) 216
8.6 Peptidomimetic Mpro Inhibitors 219
8.7 The Road to Approval of Paxlovid as an Mpro Inhibitor Drug 224
8.8 PROTACs in Antiviral Drug Discovery Through Target Degradation 227
8.9 Conclusion 228

9. Antimicrobial Peptidomimetics 237
9.1 Introduction 237
9.2 Bacterial Resistance Mechanisms 238
9.3 Definition of Antimicrobial Peptides 240
9.4 Classification of Antimicrobial Peptides 240
9.5 Structural and Physicochemical Determinants of Antimicrobial Peptides 242
9.6 Mechanism of Action of Antimicrobial Peptides 244
9.7 Representative Examples of Antimicrobial Peptides 246
9.8 Antimicrobial Peptidomimetics 248
9.9 Conclusion 253

10. Principles and Case Studies of Peptidomimetic Inhibitors of PPI 259
10.1 Introduction 259
10.2 Design of Peptidomimetic PPI Inhibitors 261
10.3 Peptidomimetics Targeting Cancer PPI 261
10.4 Case Study in Cancer: Targeting the p53-MDM2 PPI 262
10.5 Case Study in Infectious Diseases: Targeting the ACE2–SARS-CoV-2 Spike Protein PPI 270
10.6 Conclusion 278

11. Peptidomimetics Targeting the Alzheimer's Disease 285
11.1 Introduction 285
11.2 The Amyloid Hypothesis 289
11.3 Therapeutic Strategies for Alzheimer's Disease 291
11.4 BACE1 Inhibitors 299
11.5 BACE1 Inhibitors in Clinical Trials 303
11.6 Toward Selective BACE1 Inhibitors 304
11.7 Conclusion 305

12. Peptidomimetic Drugs 313
12.1 Introduction 313
12.2 Nirmatrelvir 314
12.3 Voxilaprevir 317
12.4 Brilacidin 320
12.5 Murepavadin 322
12.6 Ixazomib 324
12.7 Venetoclax 326
12.8 Lu-PSMA-617 328
12.9 Trofinetide 330
12.10 Tavilermide 332
12.11 Difelikefalin 333
12.12 Macimorelin 334

References 335
Index 341