化学
蛋白酶
体外
组合化学
肽
氨基酸
环肽
生物化学
立体化学
酶
作者
Takashi Miura,Tika R. Malla,C.D. Owen,Anthony Tumber,Lennart Brewitz,Michael A. McDonough,E. Salah,Naohiro Terasaka,Takayuki Katoh,P. Lukacik,Claire Strain-Damerell,Halina Mikolajek,Martin A. Walsh,Akane Kawamura,Christopher J. Schofield,Hiroaki Suga
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2023-05-22
卷期号:15 (7): 998-1005
被引量:11
标识
DOI:10.1038/s41557-023-01205-1
摘要
Abstract γ-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of γ-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic γ 2,4 -amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M pro ). Two kinds of cyclic γ 2,4 -amino acids, cis -3-aminocyclobutane carboxylic acid (γ 1 ) and (1 R ,3 S )-3-aminocyclopentane carboxylic acid (γ 2 ), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M pro inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ 1 at the fourth position, manifests a 5.2 nM dissociation constant. An M pro :GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ 1 interacts with the S1′ catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and M pro enabled production of a variant with a 5-fold increase in potency.
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