2. Academic Validation
  3. Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine

Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine

  • J Med Chem. 2022 Jun 9;65(11):7682-7696. doi: 10.1021/acs.jmedchem.1c02214.
Tika R Malla 1,  Lennart Brewitz 1,  Dorian-Gabriel Muntean 1,  Hiba Aslam 1,  C David Owen 2 3,  Eidarus Salah 1,  Anthony Tumber 1,  Petra Lukacik 2 3,  Claire Strain-Damerell 2 3,  Halina Mikolajek 2 3,  Martin A Walsh 2 3,  Christopher J Schofield 1
Affiliations

Affiliations

  • 1 Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, United Kingdom.
  • 2 Diamond Light Source Ltd., Harwell Science and Innovation Campus, OX11 0DE Didcot, United Kingdom.
  • 3 Research Complex at Harwell, Harwell Science and Innovation Campus, OX11 0FA Didcot, United Kingdom.
PMID: 35549342 DOI: 10.1021/acs.jmedchem.1c02214
Abstract

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.

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