Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.

Wenhao Dai, Bing Zhang, Haixia Su, Jian Li, Yao Zhao, Xiong Xie, Zhenming Jin, Fengjiang Liu, Chunpu Li, You Li, Fang Bai, Haofeng Wang, Xi Cheng, Xiaobo Cen, Shulei Hu, Xiuna Yang, Jiang Wang, Xiang Liu, Gengfu Xiao, Hualiang Jiang, Zihe Rao, Lei-Ke Zhang, Yechun Xu, Haitao Yang, Hong Liu

10.1126/science.abb4489

Research curated

Abstract

SARS-CoV-2 is the etiological agent responsible for the global COVID-19 outbreak. The main protease (M^pro) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting M^pro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The X-ray crystal structures of SARS-CoV-2 M^pro in complex with 11a or 11b, both determined at 1.5 Å resolution, showed that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of M^pro Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity, suggesting that these compounds are promising drug candidates.

Source: PubMed

Related molecules

Name	Synonyms	Genes
N-Boc-L-glutamic acid dimethyl ester 1 - Modification 11a	peptidomimetic aldehydes
N-Boc-L-glutamic acid dimethyl ester 1 - Modification 11b	peptidomimetic aldehydes
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b

Related interactions

Target	Drug	Type	Result
3C-like protease	N-Boc-L-glutamic acid dimethyl ester 1 - Modification 11a	In vitro	positive
3C-like protease	N-Boc-L-glutamic acid dimethyl ester 1 - Modification 11b	In vitro	positive