DNA encoded peptide library for SARS-CoV-2 3CL protease covalent inhibitor discovery and profiling.

Autor:	Xing Y; Biotech Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China chenshiyu@simm.ac.cn.; University of Chinese Academy of Sciences No. 19A Yuquan Road Beijing 100049 China., Zhang H; Biotech Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China chenshiyu@simm.ac.cn., Wang Y; Biotech Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China chenshiyu@simm.ac.cn., Zong Z; Biotech Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China chenshiyu@simm.ac.cn., Bogyo M; Department of Pathology, Stanford University School of Medicine Stanford CA USA., Chen S; Biotech Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China chenshiyu@simm.ac.cn.; University of Chinese Academy of Sciences No. 19A Yuquan Road Beijing 100049 China.
Jazyk:	angličtina
Zdroj:	RSC chemical biology [RSC Chem Biol] 2024 Jun 11; Vol. 5 (7), pp. 691-702. Date of Electronic Publication: 2024 Jun 11 (Print Publication: 2024).
DOI:	10.1039/d4cb00097h
Abstrakt:	Covalent protease inhibitors serve as valuable tools for modulating protease activity and are essential for investigating the functions of protease targets. These inhibitors typically consist of a recognition motif and a covalently reactive electrophile. Substrate peptides, featuring residues capable of fitting into the substrate pockets of proteases, undergo chemical modification at the carbonyl carbon of the P1 residue with an electrophile and have been widely applied in the development of covalent inhibitors. In this study, we utilized a DNA-encoded peptide library to replicate peptide binder sequences and introduced a vinyl sulfone warhead at the C-termini to construct the DNA-encoded peptide covalent inhibitor library (DEPCIL) for targeting cysteine proteases. Screening results toward 3CL protease demonstrated the efficacy of this library, not only in identifying protease inhibitors, but also in discovering amino acids that can conform to aligned protease pockets. The identified peptide sequences provide valuable insight into the amino acid preferences within substrate binding pockets, and our novel technology is indicative of the potential for similar strategies to discover covalent inhibitors and profile binding preferences of other proteases. Competing Interests: The authors declare no competing interests. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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