2. Academic Validation
  3. Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies

Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies

  • Eur J Med Chem. 2021 Oct 15:222:113584. doi: 10.1016/j.ejmech.2021.113584.
Wayne Vuong 1,  Conrad Fischer 1,  Muhammad Bashir Khan 2,  Marco J van Belkum 1,  Tess Lamer 1,  Kurtis D Willoughby 1,  Jimmy Lu 3,  Elena Arutyunova 3,  Michael A Joyce 4,  Holly A Saffran 4,  Justin A Shields 4,  Howard S Young 2,  James A Nieman 5,  D Lorne Tyrrell 4,  M Joanne Lemieux 3,  John C Vederas 6
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada.
  • 2 Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton AB, T6G 2R3, Canada.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 Department of Chemistry, University of Alberta, Edmonton AB, T6G 2G2, Canada. Electronic address: john.vederas@ualberta.ca.
PMID: 34118724 DOI: 10.1016/j.ejmech.2021.113584
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.

Keywords

COVID-19; Crystallography; GC376 analogs; Main protease; Protease inhibitor; Structure-guided design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-160832
    SARS-CoV-2 Mpro Inhibitor