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Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

Author

Listed:
  • Kangsa Amporndanai

    (University of Liverpool)

  • Xiaoli Meng

    (University of Liverpool)

  • Weijuan Shang

    (Chinese Academy of Sciences)

  • Zhenmig Jin

    (ShanghaiTech University)

  • Michael Rogers

    (University of Liverpool)

  • Yao Zhao

    (ShanghaiTech University)

  • Zihe Rao

    (ShanghaiTech University)

  • Zhi-Jie Liu

    (ShanghaiTech University)

  • Haitao Yang

    (ShanghaiTech University)

  • Leike Zhang

    (Chinese Academy of Sciences)

  • Paul M. O’Neill

    (University of Liverpool)

  • S. Samar Hasnain

    (University of Liverpool)

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.

Suggested Citation

  • Kangsa Amporndanai & Xiaoli Meng & Weijuan Shang & Zhenmig Jin & Michael Rogers & Yao Zhao & Zihe Rao & Zhi-Jie Liu & Haitao Yang & Leike Zhang & Paul M. O’Neill & S. Samar Hasnain, 2021. "Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23313-7
    DOI: 10.1038/s41467-021-23313-7
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    Cited by:

    1. Lisa-Marie Funk & Gereon Poschmann & Fabian Rabe von Pappenheim & Ashwin Chari & Kim M. Stegmann & Antje Dickmanns & Marie Wensien & Nora Eulig & Elham Paknia & Gabi Heyne & Elke Penka & Arwen R. Pear, 2024. "Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Dongtak Lee & Hyo Gi Jung & Dongsung Park & Junho Bang & Da Yeon Cheong & Jae Won Jang & Yonghwan Kim & Seungmin Lee & Sang Won Lee & Gyudo Lee & Yeon Ho Kim & Ji Hye Hong & Kyo Seon Hwang & Jeong Hoo, 2024. "Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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