Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-X_L by engaging a single-residue discrepancy.

ABSTRACT: Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-X_L can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-X_L, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify

SUBMITTER: Li F 

PROVIDER: S-EPMC10874388 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature