期刊
SCIENCE
卷 368, 期 6497, 页码 1331-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abb4489
关键词
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资金
- National Natural Science Foundation of China [21632008, 21672231, 21877118, 31970165, 91953000, 81620108027]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12040107, XDA12040201]
- Chinese Academy of Engineering [2020-CMKYGG-05]
- Science and Technology Commission of Shanghai Municipality [20431900100, 20431900200]
- National Key RAMP
- D Program of China [2017YFC0840300, 2020YFC0841400, 2020YFA0707500, 2017YFB0202604]
- Department of Science and Technology of Guangxi Zhuang Autonomous Region [2020AB40007]
- Frontier Biotechnologies Inc.
- Ma Yun Foundation [2020-CMKYGG-05]
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, M-pro, 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 a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of M-pro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
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