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Full Description
Up-to-date reference surveying the latest advances in the structural understanding of protein-protein interactions and developments in drug discovery and therapeutics
Targeting Protein-Protein Interactions for Drug Discovery provides a systematic and comprehensive overview of protein-protein interactions (PPIs), reviewing foundational concepts, advanced methodologies, and emerging therapeutic strategies, reflecting the multidisciplinary nature of PPI research.
This book discusses computational methods for predicting PPI structures, with a special emphasis on protein docking and deep learning-based approaches, diverse chemical scaffolds for PPI modulation, including foldamers as inhibitors of aberrant PPIs and sulfonyl-γ-AApeptides as novel modulators, and the development and application of stapled peptides as modulators of intracellular PPIs, offering enhanced stability, binding affinity, and cellular permeability.
Readers will also find information on cyclic peptides, focusing on their unique conformational stabilization and therapeutic potential across a range of diseases, small molecule inhibitors targeting BCL-family proteins, revealing their potential in cancer therapy, molecular glues as activators for PPIs, categorized into degraders, stabilizers, and inhibitors based on their biological effects, and the targeting of the APC-Asef interaction for drug discovery in colorectal cancer therapy, offering a case study of specificity and clinical relevance.
Targeting Protein-Protein Interactions for Drug Discovery explores sample topics including:
Challenges and strategies of drug discovery targeting PPIs, including high-throughput screening and structure-based drug design
Fluorescence resonance energy transfer (FRET) technology, a powerful tool for real-time analysis of molecular interactions in live cells
Utility of mass spectrometry (MS) for large-scale mapping of PPI networks with high sensitivity and resolution
Proximity ligation assays (PLA) for detecting PPIs in situ, emphasizing spatial precision and adaptability for multiplexed detection
Application of surface plasmon resonance (SPR) for characterizing PPI specificity, affinity, and kinetics
Exploring both classical and novel approaches to PPI characterization and modulation, Targeting Protein-Protein Interactions for Drug Discovery offers a comprehensive reference for researchers aiming to unlock the therapeutic potential of PPIs along with educators and students engaged in the study of cellular mechanisms, drug discovery, and biotechnology.
Contents
Preface xv
1 Exploring Protein-Protein Interactions: Concepts, Methods, and Implications 1
Mi Zhou and Renxiao Wang
1.1 General Concepts of Protein-Protein Interactions 1
1.2 Functional Significance of Protein-Protein Interactions 4
1.3 Methods for Analyzing Protein-Protein Interactions 12
1.4 Implications of the Basic Research on Protein-Protein Interactions 16
1.5 Conclusions and Perspectives 19
2 Overview of Drug Discovery Targeting PPI Systems 29
Hao Ma and Jian Zhang
2.1 Introduction 29
2.2 Fundamentals of Protein-Protein Interactions 30
2.3 Challenges in Targeting PPI Systems 33
2.4 Approaches in Drug Discovery Targeting PPI Systems 35
2.5 Case Studies and Success Stories 40
2.6 Conclusion 51
3 Fluorescence Resonance Energy Transfer Technology and its Applications 61
Jing-Yu Lang
3.1 Introduction 61
3.2 Mechanism of FRET 61
3.3 Applications of FRET 63
3.4 Advantages and Limitations 67
3.5 Recent Advances 68
3.6 Conclusion 70
4 Dissect Protein Interactions Using Mass Spectrometry 75
Bin Liao and Liang Zhang
4.1 Introduction 75
4.2 Affinity Purification Coupled with Mass Spectrometry (AP-MS) 76
4.3 Proximity Labeling 81
4.4 Cross-linking Mass Spectrometry (XL-MS) 84
4.5 Co-fractionation Coupled with Mass Spectrometry (CF-MS) 88
4.6 Thermal Proximity Co-aggregation (TPCA) 90
4.7 Limited Proteolysis-Mass Spectrometry (LiP-MS) 93
4.8 Conclusion and Outlook 95
Acknowledgements 96
5 Detection of Protein-Protein Interactions In Situ via Proximity Ligation Assay 105
Xinyue Zhou and Peng Zou
5.1 Introduction 105
5.2 Implementations of Proximity Ligation Assay 106
5.3 Applications of PLA for Detecting Protein-Protein Interactions 108
5.4 Conclusions and Outlooks 109
6 Application of Surface Plasmon Resonance in the Characterization of Protein-Protein Interactions 115
Yuanyuan Xie and Jianrong Xu*
6.1 Introduction 115
6.2 Applications of SPR Assays in PPI Characterization 117
6.3 Advantages and Limitations of SPR Application for PPIs 131
6.4 Future Directions 132
7 Computational Methods for Protein-Protein Interactions 139
Hao Li, Yurui Li, and Sheng-You Huang
7.1 Introduction 139
7.2 Protein-Protein Docking 140
7.3 End-to-end Structure Prediction 148
7.4 CAPRI Experiments 151
7.5 Challenges and Future Directions 154
8 Foldamers as Inhibitors of Aberrant Protein-Protein Interactions 163
Nicholas H. Stillman, Ryan A. Dohoney, Charles Z. Baysah, and Sunil Kumar
8.1 Introduction 163
8.2 The Evolution of Hamilton's Oligopyridylamides 164
8.3 Limitations of a Tedious Synthetic Route 165
8.4 OPs as Antagonists of Neurodegeneration 166
8.5 OPs Inhibit HIV Infection 168
8.6 OPs Targeting Type II Diabetes 169
8.7 OPs Targeting and Reactivating Mutant Protein in Cancer 171
8.8 Novel Synthesis of OPs and Alzheimer's Disease 173
8.9 2D-FAST 174
8.10 OQ Foldamers - Structure and Discovery 181
8.11 Synthesis of OQ Foldamers 182
8.12 OQs as Modulators of Type II Diabetes-Related aPPIs 183
8.13 Mechanistic Insights into OQ Manipulation of aPPIs 186
8.14 Chemical Diversity and Structure Modulate Efficacy of OQs 188
8.15 Modulation of Alzheimer's Disease-Related Aβ 189
8.16 OQs for the Modulation of Synucleinopathies 191
8.17 Epilogue 194
9 Application of Sulfonyl-;;-AApeptides for PPI Drug Discovery 205
Jarais Fontaine and Jianfeng Cai
9.1 Introduction 205
9.2 Application of Sulfonyl-γ-AApeptides 206
9.3 Future Directions/Conclusion 216
10 Introduction of the Application of Stapled Peptides in Protein-Protein Interactions Drug Discovery and Their Successful Examples 219
Maxwell J. Austin and Danny Hung-Chieh Chou
10.1 Introduction 219
10.2 Stapled Peptides: Structure Features and Benefits 221
10.3 Successful Applications of Stapled Peptides in Drug Discovery 227
10.4 Challenges and Limitations 232
10.5 Future Directions 234
11 Cyclic Peptides for PPI Drug Discovery 243
Hong-Gang Hu and Xiang Li
11.1 Introduction 243
11.2 α-Helix Cyclic Peptides (Stapled Peptides) 244
11.3 β-Hairpin Cyclic Peptides 253
11.4 Macrocyclic Peptides 255
11.5 Summary and Outlook 255
12 Small Molecule Inhibitors Targeting Protein-Protein Interactions in the BCL Protein 263
Wenhua Zhu, Yangbo He, Gang Chen, and Di Zhu
12.1 Introduction 263
12.2 Inhibitors of BCL-2 Family Antiapoptotic Proteins 264
12.3 Inhibitors of β-catenin/BCL9 300
12.4 Targeting BCL-6 Small Molecule Inhibitors 307
12.5 BCL-3 Inhibitors 318
12.6 BCL-10 Inhibitors 320
12.7 Summary 322
13 Molecular Glues as Activators for PPI 343
Xiangbing Qi
13.1 Introduction 343
13.2 Molecular Glues as Orthosteric PPI Stabilizers/Activators 347
13.3 Methods for MG Discovery 358
13.4 Conclusions and Outlook 364
14 Targeting APC-Asef Protein-Protein Interaction for Drug Discovery in Colorectal Cancer Therapy 373
Jie Zhong and Xiuyan Yang
14.1 Introduction 373
14.2 Structural Insights into APC-Asef Interaction 375
14.3 Current APC-Asef Inhibitor 376
14.4 A More Sensitive FP Method for Identifying Highly Active APC-Asef Inhibitors 382
14.5 Conclusions and Outlook 383
15 Computational Methods Applied to Drug Discovery of Protein-Protein Interaction Systems 389
Zhiyong Gu and Xi Cheng
15.1 Introduction 389
15.2 Computational Methods for PPI Prediction 390
15.3 Conclusions and Outlook 401
References 402
Index 409
