Peptide and Peptidomimetic Therapeutics

From Bench to Bedside

1st Edition - September 22, 2022
Editors: Nir Qvit, Samuel J.S. Rubin
Language: English
Paperback ISBN:
9 7 8 - 0 - 1 2 - 8 2 0 1 4 1 - 1
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 2 0 4 4 7 - 4

Peptide and Peptidomimetic Therapeutics: From Bench to Beside offers applied, evidence-based instruction on developing and applying peptide therapeutics in disease treatment… Read more

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Peptide and Peptidomimetic Therapeutics: From Bench to Beside offers applied, evidence-based instruction on developing and applying peptide therapeutics in disease treatment, driving drug discovery, and improving patient care. Here, researchers, clinicians and students will find tools to harness the full power of peptides and peptidomimetics and improve bioavailability, stability, efficiency and selectivity of new therapeutics and their application in treatment plans. More than 20 leaders in the field share their approaches for identifying and advancing peptide and peptidomimetic therapeutics. Topics examined run from "bench to bedside," beginning with fundamental peptide science, protein-protein interactions and peptide synthesis.

Later chapters examine modes for peptide drug delivery, including cell penetration peptide and peptidomimetic delivery, as well as the targeting of specific disease types, peptide therapeutics as applied to infectious disease, cancer, metabolic disorders, neurodegenerative disorders, and skin disorders, and antiparasitic and immunosuppressive peptidomimetics.

Cover image
Title page
Table of Contents
Copyright
List of contributors
Preface
Section 1: History
Chapter 1. Therapeutic peptides: historical perspectives and current development trends
Abstract
1.1 Introduction: The evolution of peptide therapeutics
1.2 The therapeutic peptides dataset
1.3 Clinical development timelines and benchmarks for peptides
1.4 The future of peptide therapeutics
Acknowledgments
References
Section 2: Basic science
Chapter 2. Therapeutic peptidomimetics: targeting the undruggable space
Abstract
2.1 Introduction
2.2 The “undruggable” space
2.3 Therapeutic peptidomimetics
2.4 Examples of therapeutic peptidomimetics based on applications
2.5 Conclusion
References
Chapter 3. Tailoring peptides and peptidomimetics for targeting protein–protein interactions
Abstract
3.1 Introduction
3.2 Helix mimetics
3.3 Extended structures
3.4 Loops
3.5 Summary
Acknowledgments
References
Chapter 4. Advances in peptide synthesis
Abstract
4.1 Introduction to peptides
4.2 Fluorenylmethyloxycarbonyl solid-phase peptide synthesis
4.3 Approaches for accelerated peptide synthesis
4.4 Advances in chemical synthesis of several important classes of peptides
4.5 Conclusions and outlook
Acknowledgments
References
Chapter 5. Stapled peptidomimetic therapeutics
Abstract
5.1 Introduction
5.2 Development of stapled peptide inhibitors of eukaryotic initiation factor 4E
5.3 Development of all D-amino acid stapled peptides
5.4 Development of nonhelical stapled peptides
5.5 Stapling modulates membrane permeability and aggregation propensity of peptide therapeutics
5.6 Concluding remarks
Acknowledgments
References
Chapter 6. Ring-closing metathesis/transannular cyclization to azabicyclo[X.Y.0]alkanone dipeptide turn mimics for biomedical applications
Abstract
6.1 Introduction
6.2 Ring-closing metathesis/transannular cyclization approach for making bicycles with different ring size
6.3 Installation of ring substituents to mimic side chains
6.4 Conformational analysis of unsaturated lactam and azabicyclo[X.Y.0]alkanone amino esters by X-ray crystallography illustrates relationships with β-turn geometry
6.5 Biomedical application of azabicyclo[X.Y.0]alkanone dipeptide mimics as prostaglandin F2α receptor modulators to delay preterm birth
6.6 Conclusion
Acknowledgments
References
Section 3: Drug discovery
Chapter 7. The current state of backbone cyclic peptidomimetics and their application to drug discovery
Abstract
7.1 Introduction
7.2 Peptide synthesis and backbone cyclization
7.3 Backbone cyclic peptides mimicking natural peptides
7.4 The future of backbone cyclic peptidomimetics
References
Chapter 8. Pharmacokinetics and pharmacodynamics of peptidomimetics
Abstract
8.1 Introduction
8.2 Pharmacokinetics of peptidomimetics
8.3 Absorption
8.4 Distribution
8.5 Metabolism
8.6 Excretion
8.7 Pharmacodynamics of peptidomimetics
8.8 Current perspectives
8.9 Conclusions
Acknowledgments
References
Chapter 9. Formulation of peptides and peptidomimetics
Abstract
9.1 Introduction
9.2 Challenges in formulating peptides
9.3 Formulation approaches for peptides
9.4 Formulation strategies for peptidomimetics
9.5 Future directions and conclusions
Acknowledgments
References
Chapter 10. Medical use of cell-penetrating peptides: how far have they come?
Abstract
10.1 Introduction
10.2 Application of cell-penetrating peptides in biomedicine
10.3 How to improve cell-penetrating peptide-based applications
10.4 Cell-penetrating peptides in preclinical studies
10.5 Cell-penetrating peptides in clinical studies
10.6 Concluding remarks
References
Chapter 11. Intracellular peptides as drug prototypes
Abstract
11.1 Introduction
11.2 Evidence that intracellular peptides come from proteasomal protein degradation
11.3 Experimental data on the biological significance of intracellular peptides
11.4 Evidence for biological significance of intracellular peptides in the central nervous system
11.5 Intracellular peptides profiles dramatically change in neurodegenerative diseases
11.6 Intracellular peptides disruption in anterior temporal lobe and corpus callosum of postmortem schizophrenic brains
11.7 Intracellular peptides as tools for therapeutic development
11.8 Concluding remarks
Funding
References
Chapter 12. Applications of computational three-dimensional structure prediction for antimicrobial peptides
Abstract
12.1 Introduction
12.2 What is a protein three-dimensional model?
12.3 Comparative modeling
12.4 Ab initio modeling
12.5 Contact-assisted modeling
12.6 Conclusions
Acknowledgments
References
Section 4: Therapeutic applications
Chapter 13. Knottin peptidomimetics as therapeutics
Abstract
13.1 Historical context
13.2 Why “knottin”?
13.3 The highly conserved basic structural cystine-stabilized beta-sheet motif
13.4 Knottins for drug design and engineering
13.5 Summary
References
Chapter 14. Venom peptides and peptidomimetics as therapeutics
Abstract
14.1 Introduction
14.2 Peptide categories
14.3 ATP synthase as a potent molecular drug target
14.4 Peptides as selective inhibitors of ATP synthase
14.5 Conclusion
References
Further reading
Chapter 15. Therapeutic peptides targeting protein kinase: progress, challenges, and future directions, featuring cancer and cardiovascular disease
Abstract
15.1 Introduction
15.2 Protein kinase architecture
15.3 Kinase inhibitors
15.4 Peptides targeting protein kinases
15.5 Conclusions and perspectives
Funding
References
Chapter 16. Therapeutic peptidomimetics for infectious diseases
Abstract
16.1 Introduction
16.2 Emerging peptidomimetic technologies
16.3 Peptidomimetics in the therapy of infectious diseases
16.4 Peptidomimetics in vaccine design
16.5 Peptidomimetics in diagnosis of infectious disease
16.6 Future prospects of peptidomimetics in infectious diseases
References
Chapter 17. Antiparasitic therapeutic peptidomimetics
Abstract
17.1 Introduction to parasites
17.2 Kinetoplastida parasites
17.3 Human African trypanosomiasis
17.4 Chagas disease
17.5 Leishmaniasis
17.6 Peptides as drug candidates
17.7 Antimicrobial peptides
17.8 Marine peptides
17.9 Peptides targeting vital proteins and their interactions
17.10 Peptides that target critical pathways
17.11 Peptides that target proteases
17.12 Dipeptides
17.13 Peptoids
17.14 Peptides as drug delivery agents
17.15 From antibody to peptides
17.16 Peptides as diagnostic tools for parasitic diseases
17.17 Concluding remarks
References
Chapter 18. Peptides and antibiotic resistance
Abstract
18.1 Introduction
18.2 Classification of antimicrobial peptides
18.3 Antimicrobial peptide mechanisms of action
18.4 Advantages of antimicrobial peptides compared to conventional antibiotics
18.5 Mechanisms of bacterial resistance to antimicrobial peptides
18.6 Approaches for overcoming bacterial resistance to antimicrobial peptides
18.7 Conclusion
References
Chapter 19. Antimicrobial peptides and the skin and gut microbiomes
Abstract
19.1 Introduction
19.2 Mechanism of action
19.3 Regulation of antimicrobial peptides
19.4 Antimicrobial peptides in the skin
19.5 Antimicrobial peptides in the intestine
19.6 Therapeutic opportunities
References
Chapter 20. Peptide and peptidomimetic-based vaccines
Abstract
20.1 Vaccines
20.2 Vaccine formats
20.3 Peptides or peptidomimetics as potential immunogens
20.4 Peptide-based vaccines
20.5 Advantages of peptide and peptidomimetic vaccines
20.6 Current and future perspectives
References
Chapter 21. Therapeutic peptidomimetics for cancer treatment
Abstract
21.1 Introduction
21.2 Peptidomimetics targeting proteasomal protein regulation
21.3 Peptidomimetic matrix metalloproteinase inhibitors
21.4 Aminopeptidase inhibitors
21.5 Peptidomimetics acting on the Ras-Raf-MAPK pathway
21.6 Anticancer peptidomimetics targeting HER2, HER2-HER3, and HER2-VEGF
21.7 Inhibitors of insulin-like growth factor-1 receptors
21.8 Peptidomimetic integrin inhibitors
21.9 Peptidomimetics acting on transcriptional regulation
21.10 Anticancer peptidomimetics that modulate hormone action
21.11 Peptidomimetics targeting regulation of apoptosis
21.12 Peptidomimetics targeting tubulin
21.13 Conclusion
References
Chapter 22. Immunomodulatory peptidomimetics for multiple sclerosis therapy—the story of glatiramer acetate (Copaxone)
Abstract
22.1 Introduction
22.2 Peptidomimetics for modulation of experimental autoimmune encephalomyelitis / multiple sclerosis
22.3 Approaches for blocking activation signals
22.4 The story of glatiramer acetate (Copaxone)
22.5 Immunomodulatory mechanisms
22.6 Neuroprotective repair mechanisms
22.7 Concluding remarks
References
Chapter 23. Therapeutic peptidomimetics in metabolic diseases
Abstract
23.1 Introduction
23.2 Key regulators of glucose homeostasis
23.3 The cephalic phase
23.4 The incretin effect, the duodenum, and the small intestine
23.5 Transport from the bloodstream into tissues
23.6 Reaching the endocrine pancreas
23.7 Target tissues, bioconversion, and storage
23.8 Secretion in the kidney
23.9 Diabetes
23.10 Insulin and insulin mimetics
23.11 Synthetic control of blood glucose levels
23.12 Summary
References
Chapter 24. Peptide therapeutics in anesthesiology
Abstract
24.1 Introduction
24.2 Peptide use in anesthesiology practice
24.3 Peptide-like agents
24.4 Properties to consider when administering peptides
24.5 Summary and future directions
Acknowledgments
References
Chapter 25. Cardiovascular-derived therapeutic peptidomimetics in cardiovascular disease
Abstract
25.1 Introduction
25.2 Adrenomedullin
25.3 Angiotensin II
25.4 Endothelin
25.5 Bradykinin
25.6 Natriuretic peptides
25.7 Urotensin II
25.8 Conclusions
Funding
References
Chapter 26. Noncardiovascular-derived therapeutic peptidomimetics in cardiovascular disease
Abstract
26.1 Introduction
26.2 Oxytocin and vasopressin
26.3 Calcitonin gene-related protein
26.4 Amylin
26.5 Vasoactive intestinal peptide
26.6 Glucagon-like peptide-1
26.7 Ghrelin
26.8 Salusins
26.9 Apelin/APJ system
26.10 Urocortin
26.11 Conclusion
Funding
References
Section 5: Drug development
Chapter 27. Clinical and preclinical data on therapeutic peptides
Abstract
27.1 Introduction: the evolution of peptide therapeutics
27.2 Classification of peptides
27.3 Peptide drug market and preclinical data
27.4 The future of peptide therapeutics
27.5 Concluding remarks
References
Chapter 28. Therapeutic peptides: market and manufacturing
Abstract
28.1 Historical perspectives on the therapeutic peptide market
28.2 Current perspectives on the therapeutic peptide market
28.3 Assessing the market value of therapeutic peptides
28.4 Approaches to manufacturing therapeutic peptides
28.5 Innovations in therapeutic peptide discovery and manufacturing
28.6 Conclusions
References
Further reading
Chapter 29. Future perspectives on peptide therapeutics
Abstract
29.1 Introduction
29.2 Proteolytic stability
29.3 Renal clearance
29.4 Oral bioavailability
29.5 Peptide therapeutics targeting the central nervous system
29.6 Future perspectives
References
Index

Nir Qvit

Dr. Nir Qvit completed his doctorate in organic chemistry, at the Hebrew University in 2008. His doctorate work focused on developing different strategies for synthesis of small molecules, peptides and peptidomimetics (modified peptides) for various therapeutic applications. Dr. Qvit joined Bar-Ilan University’s team of researchers in the Galilee in October 2017, and is currently the Principle Investigator of the Laboratory for Chemical Biology of Protein-Protein Interactions in the Faculty of Medicine. Dr. Qvit’s current research focuses on development of novel tools to regulate protein-protein interactions. He uses a rational approach to design and develop short peptides and peptidomimetics derived from protein regulatory domains to modulate their function in a selective manner. Dr. Qvit is a reviewer for many scientific journals, including the Journal of Medicinal Chemistry and Journal of Peptide Science; and he was a guest editor of a special issue of Current Topics in Medicinal Chemistry.

Affiliations and expertise

Principle Investigator, Laboratory for Chemical Biology of Protein-Protein Interactions, Faculty of Medicine

Samuel J.S. Rubin

Dr. “Yoni” Samuel J. S. Rubin completed his PhD in immunology at Stanford University School of Medicine in 2019, followed by postdoctoral training and MD at the same institution. His research focuses on better understanding the molecular and cellular mechanisms underlying chronic immune-mediated diseases and using this knowledge to develop safer, cheaper, and more effective tools for detecting and treating illness worldwide. In the field of mucosal immunology and immune cell trafficking, Dr. Rubin’s findings have inspired the development of novel blood-based methods for detection of gastroenterological conditions. His work has also led to the development of precision medicine therapeutics for the treatment of chronic auto-inflammatory conditions. Dr. Rubin is especially appreciative for the circuitous and often unexpected path that continues to characterize his career. Especially influential were the many instructors and mentors that inspired his dedication to teaching the student and shaped his past and ongoing endeavors. He has served as a guest editor for Current Topics in Medicinal Chemistry and continues to serve as a reviewer for numerous scientific journals. Amongst other awards and recognitions, Dr. Rubin has received the United States National Science Foundation Graduate Research Fellowship and the Hugh McDevitt Prize in Immunology.

Affiliations and expertise

Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health