Structure‐Activity Studies Reveal Scope for Optimisation of Ebselen‐Type Inhibition of SARS‐CoV‐2 Main Protease. (27th December 2021)

• Record Type: Journal Article
• Authors: Thun‐Hohenstein, Siegfried T. D.; Suits, Timothy F.; Malla, Tika R.; Tumber, Anthony; Brewitz, Lennart; Choudhry, Hani; Salah, Eidarus; Schofield, Christopher J.
• Is Part Of: ChemMedChem. Volume 17:Number 4(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-27
• Subjects: Mpro inhibition -- SARS-CoV-2 -- COVID-19 -- ebselen -- ebsulfur -- nucleophilic cysteine protease.; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100582
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The reactive organoselenium compound ebselen is being investigated for treatment of coronavirus disease 2019 (COVID‐19) and other diseases. We report structure‐activity studies on sulfur analogues of ebselen with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV‐2) main protease (M pro ), employing turnover and protein‐observed mass spectrometry‐based assays. The results reveal scope for optimisation of ebselen/ebselen derivative‐ mediated inhibition of M pro, particularly with respect to improved selectivity. Abstract : Ebselen reacts covalently with M pro multiple times, raising questions about selectivity. "Ebsulfur" compounds, in which the selenium of ebselen is replaced with sulfur, have comparable potency to ebselen but covalently react with M pro fewer times, revealing potential for optimisation of the selectivity of ebselen