Cyclized Helical Peptides Synthesis, Properties and Therapeutic Applications

by Li, Zigang; Zhao, Hui; Wan, Chuan

• ISBN13: 9783527343423
• ISBN10: 3527343423
• Edition: 1st
• Format: Hardcover
• Copyright: 2021-08-23
• Publisher: Wiley-VCH

Summary

An important and timely guide to the progress being made on constrained helical peptides

Constraint helical peptides have emerged as a solution to target previously undruggable protein-protein interactions, which feature large and complex surfaces. Cyclized Helical Peptides: Synthesis, Properties and Therapeutic Applications offers a review of the most current methodologies of constructing constrained helices. The authors noted experts on the topic include the information on the fundamental features of cyclized helical peptides and discuss their limitations. The book summarizes and explores the effects of chemical methods constructing helical peptides on helicity, binding affinity, cell penetration, and nonspecific toxicity.

The book examines the therapeutic applications of the constraint helices and includes comparison with existing small molecule modulators or antibodies. Designed as a useful resource for both those outside and inside the field. Those new to the field will find a comprehensive introduction to cyclized helical peptide and those inside the field will find a deeper understanding of the topic.

This important book:

• Offers a practical introduction to constrained helical peptides
• Includes all aspects of constrained helical peptides
• Includes information on the most recent methods that have emerged
• Presents a guide to help solve practical problems in the field

Written for academics, pharmaceutical professional, Cyclized Helical Peptides is a comprehensive guide to the developments of constrained helical peptides.

Author Biography

Zigang Li is now a professor in School of Chemical Biology and Biotechnology of Peking University. Before joining Peking University, Li worked as a postdoctoral fellow with Professor Gregory L. Verdine at Harvard University where he focused on discovery of new targets from human cancer cells for stapled peptides. Li received his PhD with Professor Chuan He at the University of Chicago in 2008 where he investigated global regulator functions on the pathogenesis of Staphylococcus aureus. Before that, Li performed his master studies at Tulane University, where he studied with Professor Chao-Jun Li on imine reactivity in aqueous media. Li completed his undergraduate degree of biophysics at The University of Science and Technology of China. Li's research interests include peptide based drug discovery and new strategies against infectious disease. He has published over 40 papers on journals including Chem. Rev., Nature Chem. Bio., PNAS, JACS, Angew. Chem. Int. Ed., Chem. Sci., Cell Chem. Biol., Chem. Commun., etc.
Hui Zhao is now a postdoc in Shenzhen GTJA Investment Group (GIG), with 3 years of experience in industry research and investment, in the field of innovative drugs and medical devices. He obtained his PhD degree in chemical genomics from Peking University under the supervision of Prof. Zigang Li in 2017. His main research direction was peptide science, with papers published in academic journals and patents applied.
Chuan Wan is a post-doc under the supervision of Prof. Zigang Li. He got his BS and Ph.D degree from China Agricultural University in 2012 and 2018, respectively. His main research interests focus on development of novel bio-orthogonal chemistry, research on peptide-stapling methodology and self-assembled materials based on stabilized a-helical peptide.

Table of Contents

PART I OVERVIEWS
1.1 Protein-protein interactions
1.1.1 Function
1.1.2 Structural basis and features
1.1.3 Targeting PPIs by small molecules
1.2 Peptides as molecular tools
1.2.1 Advantages
1.2.2 Disadvantages
1.3 Helical structures
1.3.1 Classification
1.3.2 Function
1.3.3 Characterization
1.4 Stabilization of helices via cyclization
1.4.1 Classification
1.4.2 Overview

PART II CONSTRUCTION OF CONSTRAINED HELICES
2.1 Side-chain crosslinking
(History, chemistry, features and limitations)
2.1.1 Disulfide bond
I+3, i+7, conotoxin
2.1.2 Amide or ester
2.1.3 All-hydrocarbon
I+4/3/7, stitched peptide, de alpha methylation, reduced, Moore
2.1.4 Thiol ether
I+3, Woolley, Heinis, Lin, DeGrado, Pentelute, Smith, Chou, Dawson, Li
2.1.5 Azole
Chorev, Spring, Arora
2.2 End nucleation
2.2.1 Hydrazone
2.2.2 All-hydrocarbon
Arora, Alewood
2.2.3 Disulfide bond
2.2.4 Thiol ether
2.2.5 Amide

PART III EFFECTS OF CYCLIZATION ON HELICES
3.1 Helicity
3.1.1 Ring size
3.1.2 Rigidity (alpha methylation, double bond, Z/E)
3.1.3 Substitution (chirality, group size)
3.1.4 Comparison
3.2 Binding affinity
3.2.1 Helicity
3.2.2 Cyclization position
3.2.3 Substitution
3.3 Cell permeability
3.3.1 Helicity
3.3.2 Hydrophobicity
3.3.3 Isoelectric point
3.4 Nonspecific toxicity
3.3.1 Helicity
3.3.2 Hydrophobicity
3.3.3 Isoelectric point

PART IV APPLICATIONS OF CONSTRAINED HELICES
(physiology and pathology of the target, small molecules/antibodies, structural basis, peptide modulators)
4.1 Cancer
ER, BCL-2, MDM2/X, HIF, NOTCH, RAS, beta-catenin, IRS1, Rab, EGFR, KRAS
4.2 Infectious Disease
HIV, bacteria, RSV
4.3 Nervous system disease
NMDA, Galanin, Neuropeptide Y
4.4 Respiratory system disease
Interleukin 13

PART V OUTLOOK
5.1 Methodology development
5.2 Applications