Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation.
| Autor: | Gayatri; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK christopher.schofield@chem.ox.ac.uk lennart.brewitz@chem.ox.ac.uk., Brewitz L; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK christopher.schofield@chem.ox.ac.uk lennart.brewitz@chem.ox.ac.uk., Ibbotson L; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK christopher.schofield@chem.ox.ac.uk lennart.brewitz@chem.ox.ac.uk., Salah E; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK christopher.schofield@chem.ox.ac.uk lennart.brewitz@chem.ox.ac.uk., Basak S; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK christopher.schofield@chem.ox.ac.uk lennart.brewitz@chem.ox.ac.uk., Choudhry H; Department of Biochemistry, Center for Artificial Intelligence in Precision Medicines, King Abdulaziz University Jeddah Saudi Arabia., Schofield CJ; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK christopher.schofield@chem.ox.ac.uk lennart.brewitz@chem.ox.ac.uk. |
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| Jazyk: | angličtina |
| Zdroj: | Chemical science [Chem Sci] 2024 Apr 16; Vol. 15 (20), pp. 7667-7678. Date of Electronic Publication: 2024 Apr 16 (Print Publication: 2024). |
| DOI: | 10.1039/d4sc01027b |
| Abstrakt: | 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. Competing Interests: The authors declare no competing interests. (This journal is © The Royal Society of Chemistry.) |
| Databáze: | MEDLINE |
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