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Alkyne derivatives of SARS-CoV-2 main protease inhibitors including nirmatrelvir inhibit by reacting covalently with the nucleophilic cysteine

DOI: 10.1021/acs.jmedchem.2c01627 DOI Help

Authors: Lennart Brewitz (University of Oxford) , Leo Dumjahn (University of Oxford) , Yilin Zhao (University of Oxford) , C. David Owen (Diamond Light Source; Research Complex at Harwell) , Stephen M. Laidlaw (Wellcome Centre for Human Genetics, University of Oxford) , Tika R. Malla (University of Oxford) , Dung Nguyen (Wellcome Centre for Human Genetics, University of Oxford) , Petra Lukacik (Diamond Light Source; Research Complex at Harwell) , Eidarus Salah (University of Oxford) , Adam D. Crawshaw (Newcastle University) , Anna J. Warren (Diamond Light Source) , Jose Trincao (Diamond Light Source) , Claire Strain-Damerell (Research Complex at Harwell; Diamond Light Source) , Miles W. Carroll (Wellcome Centre for Human Genetics, University of Oxford) , Martin A. 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 374

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 27088

Open Access Open Access

Abstract: Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nirmatrelvir interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins into functional nonstructural proteins. We report studies which reveal that derivatives of nirmatrelvir and other Mpro inhibitors with a nonactivated terminal alkyne group positioned similarly to the electrophilic nitrile of nirmatrelvir can efficiently inhibit isolated Mpro and SARS-CoV-2 replication in cells. Mass spectrometric and crystallographic evidence shows that the alkyne derivatives inhibit Mpro by apparent irreversible covalent reactions with the active site cysteine (Cys145), while the analogous nitriles react reversibly. The results highlight the potential for irreversible covalent inhibition of Mpro and other nucleophilic cysteine proteases by alkynes, which, in contrast to nitriles, can be functionalized at their terminal position to optimize inhibition and selectivity, as well as pharmacodynamic and pharmacokinetic properties.

Diamond Keywords: COVID-19; Viruses

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

Instruments: VMXm-Versatile Macromolecular Crystallography microfocus

Added On: 13/02/2023 08:32


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)