{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gayatri"],"funding":["Wellcome Trust","Biotechnology and Biological Sciences Research Council"],"pagination":["7667-7678"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11110133"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(20)"],"pubmed_abstract":["Enzyme inhibitors working by <i>O</i>-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 <i>S</i>-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M<sup>pro</sup>) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M<sup>pro</sup> inhibitors nirmatrelvir and simnotrelvir work <i>via</i> reversible covalent reaction of their electrophilic nitrile with the M<sup>pro</sup> nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M<sup>pro</sup> by reversible covalent reaction with Cys145 of M<sup>pro</sup>. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M<sup>pro</sup> and, by implication, other nucleophilic cysteine enzymes."],"journal":["Chemical science"],"pubmed_title":["Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease <i>via</i> reversible covalent acylation."],"pmcid":["PMC11110133"],"funding_grant_id":["106244/Z/14/Z","BB/R000344/1","BB/J003018/1"],"pubmed_authors":["Salah E","Basak S","Ibbotson L","Brewitz L","Choudhry H","Gayatri","Schofield CJ"],"additional_accession":[]},"is_claimable":false,"name":"Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease <i>via</i> reversible covalent acylation.","description":"Enzyme inhibitors working by <i>O</i>-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 <i>S</i>-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M<sup>pro</sup>) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M<sup>pro</sup> inhibitors nirmatrelvir and simnotrelvir work <i>via</i> reversible covalent reaction of their electrophilic nitrile with the M<sup>pro</sup> nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M<sup>pro</sup> by reversible covalent reaction with Cys145 of M<sup>pro</sup>. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M<sup>pro</sup> and, by implication, other nucleophilic cysteine enzymes.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 May","modification":"2026-06-03T04:26:08.065Z","creation":"2026-04-24T03:09:32.137Z"},"accession":"S-EPMC11110133","cross_references":{"pubmed":["38784729"],"doi":["10.1039/d4sc01027b"]}}