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Structural Basis for the Inhibition of Coronaviral Main Proteases by a Benzothiazole-Based Inhibitor.
Hu, Xiaohui; Lin, Cheng; Xu, Qin; Zhou, Xuelan; Zeng, Pei; McCormick, Peter J; Jiang, Haihai; Li, Jian; Zhang, Jin.
  • Hu X; School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
  • Lin C; College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China.
  • Xu Q; Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.
  • Zhou X; Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen 518118, China.
  • Zeng P; Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China.
  • McCormick PJ; Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen 518118, China.
  • Jiang H; Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China.
  • Li J; Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, UK.
  • Zhang J; School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
Viruses ; 14(9)2022 09 18.
Article in English | MEDLINE | ID: covidwho-2033152
ABSTRACT
The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV Mpros. Crystal structures of Mpros from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of Mpros from other coronaviruses. In consideration of the important role of Mpro in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral Mpro inhibitors that are safer and more effective.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptidomimetics / Middle East Respiratory Syndrome Coronavirus / COVID-19 Drug Treatment Topics: Vaccines / Variants Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: V14092075

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptidomimetics / Middle East Respiratory Syndrome Coronavirus / COVID-19 Drug Treatment Topics: Vaccines / Variants Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: V14092075