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

doi:10.1038/s41586-020-2223-y

. 2020 Jun;582(7811):289-293.

doi: 10.1038/s41586-020-2223-y. Epub 2020 Apr 9.

Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors

Zhenming Jin^#^{1

2}, Xiaoyu Du^#², Yechun Xu^#³, Yongqiang Deng^#⁴, Meiqin Liu^#⁵, Yao Zhao¹, Bing Zhang¹, Xiaofeng Li⁴, Leike Zhang⁵, Chao Peng⁶, Yinkai Duan¹, Jing Yu¹, Lin Wang¹, Kailin Yang⁷, Fengjiang Liu¹, Rendi Jiang⁵, Xinglou Yang⁵, Tian You¹, Xiaoce Liu¹, Xiuna Yang¹, Fang Bai¹, Hong Liu³, Xiang Liu⁸, Luke W Guddat⁹, Wenqing Xu^{1

6}, Gengfu Xiao⁵, Chengfeng Qin⁴, Zhengli Shi⁵, Hualiang Jiang^{10

11}, Zihe Rao^{12

13

14}, Haitao Yang¹⁵

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

Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors

Zhenming Jin et al. Nature. 2020 Jun.

. 2020 Jun;582(7811):289-293.

doi: 10.1038/s41586-020-2223-y. Epub 2020 Apr 9.

Authors

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 (M^pro) of SARS-CoV-2: M^pro 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-2^5,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M^pro 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 M^pro. Six of these compounds inhibited M^pro, 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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References

1. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020). - PubMed - PMC - DOI
1. Li, Q. et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020). - PubMed - PMC - DOI
1. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). - PubMed - PMC - DOI
1. Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). - PubMed - PMC - DOI
1. Anand, K. et al. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain. EMBO J. 21, 3213–3224 (2002). - PubMed - PMC - DOI

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[1] Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020). - PubMed - PMC - DOI

[2] Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020). - PubMed - PMC - DOI

[3] Li, Q. et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020). - PubMed - PMC - DOI

[4] Li, Q. et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020). - PubMed - PMC - DOI

[5] Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). - PubMed - PMC - DOI

[6] Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). - PubMed - PMC - DOI

[7] Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). - PubMed - PMC - DOI

[8] Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). - PubMed - PMC - DOI

[9] Anand, K. et al. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain. EMBO J. 21, 3213–3224 (2002). - PubMed - PMC - DOI

[10] Anand, K. et al. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain. EMBO J. 21, 3213–3224 (2002). - PubMed - PMC - DOI

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Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors

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Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors

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