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

Author

Listed:
  • 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
    Shandong University)

  • Chuanliu Wu

    (Xiamen University)

  • Dalei Wu

    (Shandong University)

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.

Suggested Citation

  • 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, 2024. "Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45848-1
    DOI: 10.1038/s41467-024-45848-1
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