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

DOI: 10.1021/acs.jmedchem.1c02214 DOI Help

Authors: Tika R. Malla (University of Oxford) , Lennart Brewitz (University of Oxford) , Dorian-Gabriel Muntean (University of Oxford) , Hiba Aslam (University of Oxford) , C. David Owen (Diamond Light Source) , Eidarus Salah (University of Oxford) , Anthony Tumber (University of Oxford) , Petra Lukacik (Diamond Light Source; Research Complex at Harwell) , Claire Strain-Damerell (Diamond Light Source; Research Complex at Harwell) , Halina Mikolajek (Diamond Light Source) , Martin Walsh (Diamond Light Source; Research Complex at Harwell) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 49

State: Published (Approved)
Published: May 2022
Diamond Proposal Number(s): 27088

Open Access Open Access

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.

Journal Keywords: Organic compounds; Sulfones; Inhibition; Inhibitors

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 16/05/2022 08:34


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)