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Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.
Amporndanai, Kangsa; Meng, Xiaoli; Shang, Weijuan; Jin, Zhenmig; Rogers, Michael; Zhao, Yao; Rao, Zihe; Liu, Zhi-Jie; Yang, Haitao; Zhang, Leike; O'Neill, Paul M; Samar Hasnain, S.
  • Amporndanai K; Molecular Biophysics Group, Department of Biochemistry and System Biology, Institute of System, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, UK.
  • Meng X; Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 3BX, UK.
  • Shang W; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, Hubei, China.
  • Jin Z; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Rogers M; Department of Chemistry, Faculty of Science and Engineering, University of Liverpool, Liverpool, L69 7ZD, UK.
  • Zhao Y; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Rao Z; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Liu ZJ; iHuman Institute and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Yang H; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. yanght@shanghaitech.edu.cn.
  • Zhang L; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, Hubei, China. zhangleike@wh.iov.cn.
  • O'Neill PM; Department of Chemistry, Faculty of Science and Engineering, University of Liverpool, Liverpool, L69 7ZD, UK. P.M.Oneill01@liverpool.ac.uk.
  • Samar Hasnain S; Molecular Biophysics Group, Department of Biochemistry and System Biology, Institute of System, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, UK. S.S.Hasnain@liverpool.ac.uk.
Nat Commun ; 12(1): 3061, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1387342
ABSTRACT
The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Azoles / Organoselenium Compounds / Coronavirus 3C Proteases / SARS-CoV-2 Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-23313-7

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Azoles / Organoselenium Compounds / Coronavirus 3C Proteases / SARS-CoV-2 Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-23313-7