Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation
<p>Enzyme inhibitors working by <em>O</em>-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 <em>S</em>-acylat...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Royal Society of Chemistry
2024
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| _version_ | 1811141061978882048 |
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| author | Gayatri Brewitz, L Ibbotson, L Salah, E Basak, S Choudhry, H Schofield, CJ |
| author_facet | Gayatri Brewitz, L Ibbotson, L Salah, E Basak, S Choudhry, H Schofield, CJ |
| author_sort | Gayatri |
| collection | OXFORD |
| description | <p>Enzyme inhibitors working by <em>O</em>-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 <em>S</em>-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M<small><sup>pro</sup></small>) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M<small><sup>pro</sup></small> inhibitors nirmatrelvir and simnotrelvir work <em>via</em> reversible covalent reaction of their electrophilic nitrile with the M<small><sup>pro</sup></small> nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M<small><sup>pro</sup></small> by reversible covalent reaction with Cys145 of M<small><sup>pro</sup></small>. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M<small><sup>pro</sup></small> and, by implication, other nucleophilic cysteine enzymes.</p> |
| first_indexed | 2024-09-25T04:31:54Z |
| format | Journal article |
| id | oxford-uuid:6f80c033-1a7b-41d4-9b1a-1125146956e6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:31:54Z |
| publishDate | 2024 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:6f80c033-1a7b-41d4-9b1a-1125146956e62024-08-28T13:39:10ZThiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6f80c033-1a7b-41d4-9b1a-1125146956e6EnglishSymplectic ElementsRoyal Society of Chemistry2024GayatriBrewitz, LIbbotson, LSalah, EBasak, SChoudhry, HSchofield, CJ<p>Enzyme inhibitors working by <em>O</em>-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 <em>S</em>-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M<small><sup>pro</sup></small>) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M<small><sup>pro</sup></small> inhibitors nirmatrelvir and simnotrelvir work <em>via</em> reversible covalent reaction of their electrophilic nitrile with the M<small><sup>pro</sup></small> nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M<small><sup>pro</sup></small> by reversible covalent reaction with Cys145 of M<small><sup>pro</sup></small>. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M<small><sup>pro</sup></small> and, by implication, other nucleophilic cysteine enzymes.</p> |
| spellingShingle | Gayatri Brewitz, L Ibbotson, L Salah, E Basak, S Choudhry, H Schofield, CJ Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation |
| title | Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation |
| title_full | Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation |
| title_fullStr | Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation |
| title_full_unstemmed | Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation |
| title_short | Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation |
| title_sort | thiophene fused γ lactams inhibit the sars cov 2 main protease via reversible covalent acylation |
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