Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

doi:10.1007/s13238-021-00883-2

. 2022 Sep;13(9):689-693.

doi: 10.1007/s13238-021-00883-2. Epub 2021 Oct 22.

Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

Yao Zhao^#¹, Chao Fang^#², Qi Zhang^#^{1

3

4}, Ruxue Zhang⁵, Xiangbo Zhao², Yinkai Duan¹, Haofeng Wang¹, Yan Zhu¹, Lu Feng¹, Jinyi Zhao¹, Maolin Shao¹, Xiuna Yang¹, Leike Zhang⁵, Chao Peng⁶, Kailin Yang⁷, Dawei Ma⁸, Zihe Rao^{9

10

11}, Haitao Yang¹²

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
² State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
³ CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.
⁴ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁵ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
⁶ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China.
⁷ Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USA.
⁸ State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China. madw@sioc.ac.cn.
⁹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. raozh@mail.tsinghua.edu.cn.
¹⁰ Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100091, China. raozh@mail.tsinghua.edu.cn.
¹¹ State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, Nankai University, and Tianjin Key Laboratory of Protein Sciences, Tianjin, 300071, China. raozh@mail.tsinghua.edu.cn.
¹² Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. yanght@shanghaitech.edu.cn.

^# Contributed equally.

PMID: 34687004
PMCID: PMC8533666
DOI: 10.1007/s13238-021-00883-2

Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

Yao Zhao et al. Protein Cell. 2022 Sep.

. 2022 Sep;13(9):689-693.

doi: 10.1007/s13238-021-00883-2. Epub 2021 Oct 22.

Authors

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
² State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
³ CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.
⁴ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁵ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
⁶ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China.
⁷ Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USA.
⁸ State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China. madw@sioc.ac.cn.
⁹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. raozh@mail.tsinghua.edu.cn.
¹⁰ Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, 100091, China. raozh@mail.tsinghua.edu.cn.
¹¹ State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, Nankai University, and Tianjin Key Laboratory of Protein Sciences, Tianjin, 300071, China. raozh@mail.tsinghua.edu.cn.
¹² Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. yanght@shanghaitech.edu.cn.

^# Contributed equally.

PMID: 34687004
PMCID: PMC8533666
DOI: 10.1007/s13238-021-00883-2

No abstract available

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Figures

**Figure 1**
**The structure of SARS-CoV-2 M**^pro in complex with PF-07321332. (A) A putative inhibition mechanism of PF-07321332. The catalytic C145 and H41 of SARS-CoV-2 M^pro are highlighted with dark blue squares. P1’, P1, P2 and P4 are highlighted with green squares. (B) The overall structure of a SARS-CoV-2 M^pro protomer. The three domains of M^pro are labeled. The substrate-binding pocket is located within the black box. PF-07321332 is shown as ball-and-stick model with the carbon atoms in bright green, oxygen atoms in bright red, and nitrogen atoms in blue, and fluorine atom in brown. (C) The zoom-in view of the substrate-binding pocket. PF-07321332 forms a covalent bond to C145. Three substrate-binding subsites (S1, S2 and S4) are labeled. (D) The Sγ atom of the catalytic C145 forms a 1.8-Å C-S covalent bond with the nitrile carbon of PF-07321332. The 2F_o-F_c density map contoured at 1.2σ is shown in the light blue mesh. (E) The catalytic C145 in another state where it does not form a covalent bond with PF-07321332. The 2F_o-F_c density map contoured at 1.2σ is shown in the light blue mesh. (F) The detailed binding model in the SARS-CoV-2 M^pro-PF07321332 complex structure. The residues that participate in inhibitor binding are shown as sticks. (G) Schematic diagram of the interactions between PF-07321332 and SARS-CoV-2 M^pro. (H) The polder density map of PF-07321332, which is colored as the light blue mesh and contoured at 3.0 σ. (I) The comparison of SARS-CoV-2 M^pro-PF07321332 complex structure with that of SARS-CoV-2 M^pro-boceprevir. (J) The molecular weights of apo SARS-CoV-2 M^pro and PF-07321332 treated M^pro determined from tandem mass spectrometry. The mass shift (∆m) of the protein is labeled

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References

1. Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, Beutler N, Binder J, Chen E, Eng H, et al. Discovery of a novel inhibitor of coronavirus 3CL protease for the potential treatment of COVID-19. BbioRxiv. 2021;1:2020–2029. - PMC - PubMed
1. Cui W, Yang K, Yang H. Recent progress in the drug development targeting SARS-CoV-2 main protease as treatment for COVID-19. Front Mol Biosci. 2020;7:616341. doi: 10.3389/fmolb.2020.616341. - DOI - PMC - PubMed
1. Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368:1331–1335. doi: 10.1126/science.abb4489. - DOI - PMC - PubMed
1. Fu L, Ye F, Feng Y, Yu F, Wang Q, Wu Y, Zhao C, Sun H, Huang B, Niu P, et al. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nat Commun. 2020;11:4417. doi: 10.1038/s41467-020-18233-x. - DOI - PMC - PubMed
1. Hoffman RL, Kania RS, Brothers MA, Davies JF, Ferre RA, Gajiwala KS, He M, Hogan RJ, Kozminski K, Li LY, et al. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J Med Chem. 2020;63:12725–12747. doi: 10.1021/acs.jmedchem.0c01063. - DOI - PMC - PubMed

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[1] Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, Beutler N, Binder J, Chen E, Eng H, et al. Discovery of a novel inhibitor of coronavirus 3CL protease for the potential treatment of COVID-19. BbioRxiv. 2021;1:2020–2029. - PMC - PubMed

[2] Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, Beutler N, Binder J, Chen E, Eng H, et al. Discovery of a novel inhibitor of coronavirus 3CL protease for the potential treatment of COVID-19. BbioRxiv. 2021;1:2020–2029. - PMC - PubMed

[3] Cui W, Yang K, Yang H. Recent progress in the drug development targeting SARS-CoV-2 main protease as treatment for COVID-19. Front Mol Biosci. 2020;7:616341. doi: 10.3389/fmolb.2020.616341. - DOI - PMC - PubMed

[4] Cui W, Yang K, Yang H. Recent progress in the drug development targeting SARS-CoV-2 main protease as treatment for COVID-19. Front Mol Biosci. 2020;7:616341. doi: 10.3389/fmolb.2020.616341. - DOI - PMC - PubMed

[5] Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368:1331–1335. doi: 10.1126/science.abb4489. - DOI - PMC - PubMed

[6] Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368:1331–1335. doi: 10.1126/science.abb4489. - DOI - PMC - PubMed

[7] Fu L, Ye F, Feng Y, Yu F, Wang Q, Wu Y, Zhao C, Sun H, Huang B, Niu P, et al. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nat Commun. 2020;11:4417. doi: 10.1038/s41467-020-18233-x. - DOI - PMC - PubMed

[8] Fu L, Ye F, Feng Y, Yu F, Wang Q, Wu Y, Zhao C, Sun H, Huang B, Niu P, et al. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nat Commun. 2020;11:4417. doi: 10.1038/s41467-020-18233-x. - DOI - PMC - PubMed

[9] Hoffman RL, Kania RS, Brothers MA, Davies JF, Ferre RA, Gajiwala KS, He M, Hogan RJ, Kozminski K, Li LY, et al. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J Med Chem. 2020;63:12725–12747. doi: 10.1021/acs.jmedchem.0c01063. - DOI - PMC - PubMed

[10] Hoffman RL, Kania RS, Brothers MA, Davies JF, Ferre RA, Gajiwala KS, He M, Hogan RJ, Kozminski K, Li LY, et al. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J Med Chem. 2020;63:12725–12747. doi: 10.1021/acs.jmedchem.0c01063. - DOI - PMC - PubMed

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Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

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Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

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