Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CL.sup.pro covalent inhibitors.

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Publisher: Elsevier B.V.
Document Type: Report; Brief article
Length: 309 words

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Abstract :

Keywords SARS-CoV2; 3CLpro; Mpro; covalent inhibitors Highlights * Covalent docking was used to design SARS-CoV-2 3CLpro inhibitors. * A micromolar non-covalent SARS-CoV 3CLpro inhibitor was converted into a submicromolar SARS-CoV-2 3CLpro covalent inhibitor. * A set of warheads was evaluated and vinyl sulfonamide and alkynylamide were identified as promising warheads. * Crystallography confirmed the docking-proposed mode of binding. * SAR studies led to improved potency. Abstract Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CL.sup.pro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CL.sup.pro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CL.sup.pro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform. Author Affiliation: (a) Department of Chemistry, McGill University, 801 Sherbrooke St W, Montreal, QC, Canada, H3A 0B8 (b) Department of Biochemistry, McGill University, 3649 Promenade Sir William Osler Montreal, QC, Canada, H3G 0B1 * Corresponding authors. Article History: Received 30 September 2021; Revised 17 November 2021; Accepted 1 December 2021 (footnote)1 These authors contributed equally to this work. Byline: Julia K. Stille (a,1), Jevgenijs Tjutrins (a,1), Guanyu Wang (a,1), Felipe A. Venegas (a,1), Christopher Hennecker (a), Andrés M. Rueda (a), Itai Sharon (b), Nicole Blaine (a), Caitlin E. Miron (a), Sharon Pinus (a), Anne Labarre (a), Jessica Plescia (a), Mihai Burai Patrascu (a), Xiaocong Zhang (a), Alexander S. Wahba (a), Danielle Vlaho (a), Mitchell J. Huot (a), T. Martin Schmeing (b), Anthony K. Mittermaier [anthony.mittermaier@mcgill.ca] (a,*), Nicolas Moitessier [nicolas.moitessier@mcgill.ca] (a,*)

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Gale Document Number: GALE|A689719180