CHAPTER 6: Hydrogen Bond Surrogate Stabilized Helices as Protein-Protein Interaction Inhibitors

Daniel Yoo, Paramjit S. Arora

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Protein-protein interactions (PPIs) are often misregulated in disease and are attractive targets for drug discovery. Several strategies that rely on high throughput screening and rational design for developing inhibitors of protein complex formation have been described. We have pursued a rational design approach that captures the conformation of the critical binding epitope from one interacting protein partner. This approach builds on the hypothesis that binding epitopes are often defined by a handful of residues that dominate the binding energy landscape, and that mimicry of these residues would result in small- to medium-sized inhibitors of the chosen target. Here, we review our approach to develop helical mimics that capture the backbone conformation and interacting residues of the most frequently occurring secondary structure motif at protein interfaces. We describe a hydrogen bond surrogate (HBS) approach to constrain peptides into the α-helical geometry. HBS α-helices have been extensively characterized in vitro and in vivo and shown to successfully reproduce helical protein epitopes. The HBS approach has yielded effective inhibitors for multiple PPI complexes. We will continue to evolve to address the existing challenges of peptide-based therapeutics.

Original languageEnglish (US)
Title of host publicationProtein Degradation with New Chemical Modalities
Subtitle of host publicationSuccessful Strategies in Drug Discovery and Chemical Biology
EditorsSiddhartha Roy, Haian Fu
PublisherRoyal Society of Chemistry
Pages124-146
Number of pages23
Edition78
ISBN (Electronic)9781788011877, 9781788015479, 9781788016865, 9781788018012, 9781788018760
DOIs
StatePublished - 2021

Publication series

NameRSC Drug Discovery Series
Number78
Volume2021-January
ISSN (Print)2041-3203
ISSN (Electronic)2041-3211

ASJC Scopus subject areas

  • Drug Discovery

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