Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Nature communications, 2021-05, Vol.12 (1), p.3061-3061, Article 3061

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2021

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M pro ), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M pro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M pro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M pro 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 M pro 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. Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (M pro ). Here, the authors co-crystallised M pro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.