Journal article
Penicillin derivatives inhibit the SARS-CoV-2 main protease by reaction with its nucleophilic cysteine
- Abstract:
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The SARS-CoV-2 main protease (Mpro) 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 Mpro inhibitors and investigate their mechanism of inhibition using mass spectrometric and crystallographic analyses. The results suggest that β-lactams have considerable potential as Mpro 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 4.0MB, Terms of use)
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- Publisher copy:
- 10.1021/acs.jmedchem.1c02214
Authors
- Grant:
- BB/R000344/1
- BB/J003018/1
- 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:
- EISSN:
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1520-4804
- ISSN:
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0022-2623
- Pmid:
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35549342
- Language:
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English
- Keywords:
- Pubs id:
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1259829
- Local pid:
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pubs:1259829
- Deposit date:
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2023-01-13
Terms of use
- Copyright holder:
- Malla et al.
- Copyright date:
- 2022
- Rights statement:
- © 2022 The Authors. Published by American Chemical Society. This is an open access article published under CC BY 4.0.
- Notes:
- This research was funded in part by the Wellcome Trust (106244/Z/14/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
- Licence:
- CC Attribution (CC BY)
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