Binary combinatorial scanning reveals potent poly-alanine-substituted inhibitors of protein-protein interactions.

ABSTRACT: Establishing structure-activity relationships is crucial to understand and optimize the activity of peptide-based inhibitors of protein-protein interactions. Single alanine substitutions provide limited information on the residues that tolerate simultaneous modifications with retention of biological activity. To guide optimization of peptide binders, we use combinatorial peptide libraries of over 4,000 variants-in which each position is varied with either the wild-type residue or alanine-with a label-free affinity selection platform to study protein-ligand interactions. Applying this platform to a peptide binder to the oncogenic protein MDM2, several multi-alanine-substituted analogs with picomolar binding affinity were discovered. We reveal a non-additive substitution pattern in the selec

SUBMITTER: Ye X 

PROVIDER: S-EPMC9814900 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature