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Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies.
Vuong, Wayne; Fischer, Conrad; Khan, Muhammad Bashir; van Belkum, Marco J; Lamer, Tess; Willoughby, Kurtis D; Lu, Jimmy; Arutyunova, Elena; Joyce, Michael A; Saffran, Holly A; Shields, Justin A; Young, Howard S; Nieman, James A; Tyrrell, D Lorne; Lemieux, M Joanne; Vederas, John C.
  • Vuong W; Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada.
  • Fischer C; Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada.
  • Khan MB; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton AB, T6G 2R3, Canada.
  • van Belkum MJ; Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada.
  • Lamer T; Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada.
  • Willoughby KD; Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada.
  • Lu J; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Arutyunova E; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Joyce MA; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Saffran HA; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Shields JA; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Young HS; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton AB, T6G 2R3, Canada.
  • Nieman JA; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Tyrrell DL; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Lemieux MJ; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton AB, T6G 2R3, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB, T6G 2E1, Canada.
  • Vederas JC; Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada. Electronic address: john.vederas@ualberta.ca.
Eur J Med Chem ; 222: 113584, 2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1252810
ABSTRACT
Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (Mpro) to cleave viral proteins. Consequently, Mpro is a target for antiviral agents. We and others previously demonstrated that GC376, a bisulfite prodrug with efficacy as an anti-coronaviral agent in animals, is an effective inhibitor of Mpro in SARS-CoV-2. Here, we report structure-activity studies of improved GC376 derivatives with nanomolar affinities and therapeutic indices >200. Crystallographic structures of inhibitor-Mpro complexes reveal that an alternative binding pocket in Mpro, S4, accommodates the P3 position. Alternative binding is induced by polar P3 groups or a nearby methyl. NMR and solubility studies with GC376 show that it exists as a mixture of stereoisomers and forms colloids in aqueous media at higher concentrations, a property not previously reported. Replacement of its Na+ counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for Mpro inhibitor design.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrrolidines / Sulfonic Acids / Cysteine Proteinase Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: Eur J Med Chem Year: 2021 Document Type: Article Affiliation country: J.ejmech.2021.113584

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrrolidines / Sulfonic Acids / Cysteine Proteinase Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: Eur J Med Chem Year: 2021 Document Type: Article Affiliation country: J.ejmech.2021.113584