A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase

文献信息

发布日期 2023-11-21

DOI 10.1039/D3SC03331G

影响因子 9.825

作者

Pedro Zuazua-Villar, Oliwia Koczy, Andrew J. Counsell, Stephen J. Walsh, Naomi S. Robertson, David R. Spring, Jessica A. Downs, Marko Hyvönen

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摘要

Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment.

期刊推荐

Current Topics in Medicinal Chemistry

Medicinal Chemistry

Nature Methods

Nature Materials

Letters in Organic Chemistry

Organic & Biomolecular Chemistry

Phytochemistry Reviews

Letters in Drug Design & Discovery

Molecular Cancer Therapeutics

Catalysis Communications

来源期刊

Chemical Science

CiteScore: 14.4

自引率: 3.9%

年发文量: 1413

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A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase

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Chemical Science

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