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

Fengwei Li (), Junjie Liu, Chao Liu, Ziyan Liu, Xiangda Peng, Yinyue Huang, Xiaoyu Chen, Xiangnan Sun, Sen Wang, Wei Chen, Dan Xiong, Xiaotong Diao, Sheng Wang, Jingjing Zhuang, Chuanliu Wu () and Dalei Wu ()
Additional contact information
Fengwei Li: Shandong University
Junjie Liu: Xiamen University
Chao Liu: Shandong University
Ziyan Liu: Xiamen University
Xiangda Peng: Shanghai Zelixir Biotech Company Ltd.
Yinyue Huang: Shandong University
Xiaoyu Chen: Shandong University
Xiangnan Sun: Shandong University
Sen Wang: Shandong University
Wei Chen: Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital
Dan Xiong: Xiamen Lifeint Technology Company Ltd.
Xiaotong Diao: Shandong University
Sheng Wang: Shanghai Zelixir Biotech Company Ltd.
Jingjing Zhuang: Shandong University
Chuanliu Wu: Xiamen University
Dalei Wu: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL 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-XL, 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 a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular “switch” that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

Date: 2024
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DOI: 10.1038/s41467-024-45848-1

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