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Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy.
Li, Fengwei; Liu, Junjie; Liu, Chao; Liu, Ziyan; Peng, Xiangda; Huang, Yinyue; Chen, Xiaoyu; Sun, Xiangnan; Wang, Sen; Chen, Wei; Xiong, Dan; Diao, Xiaotong; Wang, Sheng; Zhuang, Jingjing; Wu, Chuanliu; Wu, Dalei.
Affiliation
  • Li F; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China. lifengwei@sdu.edu.cn.
  • Liu J; The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
  • Liu C; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Liu Z; The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
  • Peng X; Shanghai Zelixir Biotech Company Ltd., Shanghai, 200030, China.
  • Huang Y; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Chen X; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Sun X; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Wang S; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Chen W; Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, 200127, China.
  • Xiong D; Xiamen Lifeint Technology Company Ltd., Xiamen, 361005, China.
  • Diao X; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Wang S; Shanghai Zelixir Biotech Company Ltd., Shanghai, 200030, China.
  • Zhuang J; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
  • Wu C; Marine College, Shandong University, Weihai, 264209, China.
  • Wu D; The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China. chlwu@xmu.edu.cn.
Nat Commun ; 15(1): 1476, 2024 Feb 17.
Article in En | MEDLINE | ID: mdl-38368459
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides, Cyclic / Antineoplastic Agents Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides, Cyclic / Antineoplastic Agents Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: