Impact of Hydrogen‐Bond Surrogate Model on Helix Stabilization and Development of Protein‐Protein Interaction Inhibitors

Abstract

Protein-protein interactions (PPIs) involved in several diseases are predominantly mediated through short helical peptides. Unlike small molecules, due to the extended surface, the chemically constrained peptides with proper helical conformation can modulate the PPIs and thus contribute to the future drug developments. Several model systems have been introduced in the past to induce the helical structure in short peptides. Incorporating the unnatural constraints by various protocols has been excellent in biasing helical conformation and improving the proteolytic stability and the cell permeability of peptides. Hydrogen-bond surrogate (HBS) is one of such well-known protocols to mimic helical surfaces in numerous peptide sequences. Unlike 'Stapled' peptides, HBSmodel replaces the main-chain i + 4!i hydrogen bonding interaction with a covalent surrogate and retains the side-chain functionality intact, which is beneficial for targeting multi-faced PPIs. This review focuses on the chemistry behind the development of the HBS-stabilized peptides, its biophysical characterizations, and numerous biological applications. Furthermore, this review will provide a broad overview of the HBS-model to attract chemical biologists to target multifaced 'difficult' PPIs.