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Structure-Based Discovery and Structural Basis of a Novel Broad-Spectrum Natural Product against the Main Protease of Coronavirus.
Zhang, Yuting; Gao, Hongxia; Hu, Xiaohui; Wang, Qisheng; Zhong, Fanglin; Zhou, Xuelan; Lin, Cheng; Yang, Yang; Wei, Junkang; Du, Weian; Huang, Huaiqiu; Zhou, Huan; He, Wei; Zhang, Hua; Zhang, Yuting; McCormick, Peter J; Fu, Jinheng; Wang, Dan; Fu, Yang; Lu, Xiaolu; Zhang, Tengfei; Duan, Jingjing; Qin, Bingjie; Jiang, Haihai; Luo, Jun; Zhang, Yan; Chen, Qi; Luo, Qunfeng; Cheng, Lin; Zhang, Zheng; Zhang, Jin; Li, Jian.
  • Zhang Y; School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Gao H; College of Pharmaceutical Sciences, Gannan Medical Universitygrid.440714.2, Ganzhou, China.
  • Hu X; The Second Affiliated Hospital of Nanchang Universitygrid.260463.5, Nanchang, China.
  • Wang Q; School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Zhong F; Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
  • Zhou X; Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen, China.
  • Lin C; Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou, China.
  • Yang Y; School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Wei J; College of Pharmaceutical Sciences, Gannan Medical Universitygrid.440714.2, Ganzhou, China.
  • Du W; Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen, China.
  • Huang H; Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou, China.
  • Zhou H; Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
  • He W; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
  • Zhang H; Department of Dermatology and Venereology, Third Affiliated Hospital of Sun Yat-sen Universitygrid.412558.f, Guangzhou, Guangdong, People's Republic of China.
  • Zhang Y; Department of Dermatology and Venereology, Third Affiliated Hospital of Sun Yat-sen Universitygrid.412558.f, Guangzhou, Guangdong, People's Republic of China.
  • McCormick PJ; Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
  • Fu J; College of Pharmaceutical Sciences, Gannan Medical Universitygrid.440714.2, Ganzhou, China.
  • Wang D; School of Biological Science and Technology, University of Jinan, Jinan, China.
  • Fu Y; School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Lu X; William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Zhang T; Jiangxi-OAI Joint Research Institute, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Duan J; Key Lab for Agro-product Processing and Quality Control of Nanchang City, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, China.
  • Qin B; School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • Jiang H; College of Pharmaceutical Sciences, Gannan Medical Universitygrid.440714.2, Ganzhou, China.
  • Luo J; Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • Zhang Y; Human Aging Research Institute, School of Life Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Chen Q; Hyper-Dimension Insight Pharmaceuticals Ltd., Beijing, China.
  • Luo Q; School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
  • Cheng L; The Second Affiliated Hospital of Nanchang Universitygrid.260463.5, Nanchang, China.
  • Zhang Z; The Second Affiliated Hospital of Nanchang Universitygrid.260463.5, Nanchang, China.
  • Zhang J; The Second Affiliated Hospital of Nanchang Universitygrid.260463.5, Nanchang, China.
  • Li J; School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
J Virol ; 96(1): e0125321, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1639525
ABSTRACT
Over the past 20 years, the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2 emerged, causing severe human respiratory diseases throughout the globe. Developing broad-spectrum drugs would be invaluable in responding to new, emerging coronaviruses and to address unmet urgent clinical needs. Main protease (Mpro; also known as 3CLpro) has a major role in the coronavirus life cycle and is one of the most important targets for anti-coronavirus agents. We show that a natural product, noncovalent inhibitor, shikonin, is a pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, human coronavirus (HCoV)-HKU1, HCoV-NL63, and HCoV-229E with micromolar half maximal inhibitory concentration (IC50) values. Structures of the main protease of different coronavirus genus, SARS-CoV from the betacoronavirus genus and HCoV-NL63 from the alphacoronavirus genus, were determined by X-ray crystallography and revealed that the inhibitor interacts with key active site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses as well as emerging coronaviruses of the future. Given the importance of the main protease for coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. IMPORTANCE The current pandemic has created an urgent need for broad-spectrum inhibitors of SARS-CoV-2. The main protease is relatively conservative compared to the spike protein and, thus, is one of the most promising targets in developing anti-coronavirus agents. We solved the crystal structures of the main protease of SARS-CoV and HCoV-NL63 that bound to shikonin. The structures provide important insights, have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad-spectrum anti-coronavirus ligands as new therapeutic agents.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases Type of study: Prognostic study Language: English Journal: J Virol Year: 2022 Document Type: Article Affiliation country: Jvi.01253-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases Type of study: Prognostic study Language: English Journal: J Virol Year: 2022 Document Type: Article Affiliation country: Jvi.01253-21