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

2020; American Association for the Advancement of Science; Volume: 368; Issue: 6497 Linguagem: Inglês

10.1126/science.abb4489

1095-9203

Wenhao Dai, Bing Zhang, Xia-Ming Jiang, Haixia Su, Jian Li, Yao Zhao, Xiong Xie, Zhenming Jin, Jingjing Peng, 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, Leike Zhang, Yechun Xu, Haitao Yang, Hong Liu,

COVID-19 Clinical Research Studies

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, 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 Mpro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.