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

European Journal of Medicinal Chemistry
Wayne VuongJ. C. Vederas

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.

References

Jun 27, 1995·Biochemistry·B A MalcolmD V Santi
Oct 3, 1999·Antimicrobial Agents and Chemotherapy·A K PatickS T Worland
Feb 5, 1997·Chemical Reviews·Hans-Hartwig Otto, Tanja Schirmeister
Aug 25, 2006·Journal of Virology·Stanley G SawickiStuart G Siddell
Sep 3, 2010·Nature Reviews. Drug Discovery·Marcin Drag, Guy S Salvesen
Dec 28, 2010·Journal of Magnetic Resonance·Adolfo BotanaGareth A Morris
Dec 12, 2012·Bioorganic & Medicinal Chemistry Letters·Sivakoteswara Rao MandadapuWilliam C Groutas
Oct 22, 2018·Antiviral Research·Krishani Dinali PereraYunjeong Kim
Jan 17, 2019·The Journal of Chemical Physics·Lorenzo CostigliolaJeppe C Dyre
Jul 17, 2020·Antimicrobial Agents and Chemotherapy·Hui-Chen HungJohn Tsu-An Hsu
Aug 29, 2020·Nature Communications·Wayne VuongM Joanne Lemieux
Feb 12, 2021·ACS Infectious Diseases·Kas SteutenMatthew Bogyo

❮ Previous
Next ❯

Software Mentioned

OpenVNMRJ
Coot
Phenix
Ice
Web
PyMOL

Related Concepts

Related Feeds

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.