Design and Application of an alpha-Helix-Mimetic Scaffold Based on an Oligoamide-Foldamer Strategy: Antagonism of the Bak BH3/Bcl-xL Complex

摘要

The design of low-molecular-weight ligands (<750 Da) that recognize protein surfaces and subsequently disrupt protein-protein interactions is an area of intense research.~[1] Current strategies for identifying small-molecule protein-surface antagonists primarily involve the use of combinatorial methods. However, more recently, rational structure-based-design approaches have been presented.~[1] Given the ubiquitous role of alpha helices in mediating protein-protein interactions, we sought to explore the de novo design of scaffolds that present side-chain functonality with similar distance and angular constraints to that found along one face of an alpha-helical secondary structure.~[2]