Penicillin derivatives inhibit the SARS-CoV-2 main protease by reaction with its nucleophilic cysteine

Journal article

The SARS-CoV-2 main protease (M^pro) is a medicinal chemistry target for COVID-19 treatment. Given the clinical efficacy of β-lactams as inhibitors of bacterial nucleophilic enzymes, they are of interest as inhibitors of viral nucleophilic serine and cysteine proteases. We describe the synthesis of penicillin derivatives which are potent M^pro inhibitors and investigate their mechanism of inhibition using mass spectrometric and crystallographic analyses. The results suggest that β-lactams have considerable potential as M^pro inhibitors via a mechanism involving reaction with the nucleophilic cysteine to form a stable acyl–enzyme complex as shown by crystallographic analysis. The results highlight the potential for inhibition of viral proteases employing nucleophilic catalysis by β-lactams and related acylating agents.

Authors: Malla, TR; Brewitz, L; Muntean, D-G; Aslam, H; Owen, CD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry More from this journal
• Volume: 65
• Issue: 11
• Pages: 7682-7696
• Place of publication: United States
• Publication date: 2022-05-12
• Acceptance date: 2022-05-12
• DOI: 10.1021/acs.jmedchem.1c02214
• EISSN: 1520-4804
• ISSN: 0022-2623
• Pmid: 35549342
• Language: English
• Keywords: cysteine endopeptidases; antiviral agents; SARS-CoV-2; coronavirus 3C proteases; beta-lactams; penicillins; humans; FFR; protease inhibitors; cysteine; COVID-19