Structure‐Activity Studies Reveal Scope for Optimisation of Ebselen‐Type Inhibition of SARS‐CoV‐2 Main Protease

• Published in: ChemMedChem Vol. 17; no. 4; pp. e202100582 - n/a
• Main Authors: Thun‐Hohenstein, Siegfried T. D., Suits, Timothy F., Malla, Tika R., Tumber, Anthony, Brewitz, Lennart, Choudhry, Hani, Salah, Eidarus, Schofield, Christopher J.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 16.02.2022; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Chemistry, Medicinal; Communication; Communications; Coronavirus 3C Proteases - antagonists & inhibitors; Coronaviruses; COVID-19; COVID-19 - virology; ebselen; ebsulfur; Humans; Isoindoles - chemistry; Isoindoles - pharmacology; Life Sciences & Biomedicine; Mass spectrometry; Mass spectroscopy; Mpro inhibition; nucleophilic cysteine protease; Optimization; Organoselenium compounds; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Pharmacology & Pharmacy; Protease; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein turnover; Proteinase; SARS-CoV-2; SARS-CoV-2 - enzymology; Science & Technology; Selectivity; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Structure-Activity Relationship; Sulfur; Viral diseases; COVID-19; DRUG; SARS-CoV-2; ebselen; nucleophilic cysteine protease; M-pro inhibition; ebsulfur; Mpro inhibition
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202100582

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 (Mpro), employing turnover and protein‐observed mass spectrometry‐based assays. The results reveal scope for optimisation of ebselen/ebselen derivative‐ mediated inhibition of Mpro, particularly with respect to improved selectivity. Ebselen reacts covalently with Mpro 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 Mpro fewer times, revealing potential for optimisation of the selectivity of ebselen