2. Academic Validation
  3. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

  • Nature. 2020 Jun;582(7811):289-293. doi: 10.1038/s41586-020-2223-y.
Zhenming Jin  # 1 2,  Xiaoyu Du  # 2,  Yechun Xu  # 3,  Yongqiang Deng  # 4,  Meiqin Liu  # 5,  Yao Zhao 1,  Bing Zhang 1,  Xiaofeng Li 4,  Leike Zhang 5,  Chao Peng 6,  Yinkai Duan 1,  Jing Yu 1,  Lin Wang 1,  Kailin Yang 7,  Fengjiang Liu 1,  Rendi Jiang 5,  Xinglou Yang 5,  Tian You 1,  Xiaoce Liu 1,  Xiuna Yang 1,  Fang Bai 1,  Hong Liu 3,  Xiang Liu 8,  Luke W Guddat 9,  Wenqing Xu 1 6,  Gengfu Xiao 5,  Chengfeng Qin 4,  Zhengli Shi 5,  Hualiang Jiang 10 11,  Zihe Rao 12 13 14,  Haitao Yang 15
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2 Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
  • 3 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
  • 5 CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
  • 6 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China.
  • 7 Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
  • 8 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin, China.
  • 9 School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, Queensland, Australia.
  • 10 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. hljiang@simm.ac.cn.
  • 11 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. hljiang@simm.ac.cn.
  • 12 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. raozh@mail.tsinghua.edu.cn.
  • 13 Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China. raozh@mail.tsinghua.edu.cn.
  • 14 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin, China. raozh@mail.tsinghua.edu.cn.
  • 15 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. yanght@shanghaitech.edu.cn.
  • # Contributed equally.
PMID: 32272481 DOI: 10.1038/s41586-020-2223-y
Abstract

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key Enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising Antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.

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