Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation

Journal article

Enzyme inhibitors working by O-acylation of nucleophilic serine residues are of immense medicinal importance, as exemplified by the β-lactam antibiotics. By contrast, inhibition of nucleophilic cysteine enzymes by S-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M^pro) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M^pro inhibitors nirmatrelvir and simnotrelvir work via reversible covalent reaction of their electrophilic nitrile with the M^pro nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M^pro by reversible covalent reaction with Cys145 of M^pro. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M^pro and, by implication, other nucleophilic cysteine enzymes.

Authors: Gayatri; Brewitz, L; Ibbotson, L; Salah, E; Basak, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: Chemical Science
• Volume: 15
• Issue: 20
• Pages: 7667-7678
• Publication date: 2024-04-16
• Acceptance date: 2024-04-15
• DOI: 10.1039/d4sc01027b
• EISSN: 2041-6539
• ISSN: 2041-6520
• Pmid: 38784729
• Language: English
• Keywords: FFR