tetano
Editor, Senior Moderator
Eur J Med Chem
. 2021 May 30;222:113584.
doi: 10.1016/j.ejmech.2021.113584. Online ahead of print.
Improved SARS-CoV-2 M [SUP]pro[/SUP] inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies
Wayne Vuong[SUP] 1 [/SUP], Conrad Fischer[SUP] 1 [/SUP], Muhammad Bashir Khan[SUP] 2 [/SUP], Marco J van Belkum[SUP] 1 [/SUP], Tess Lamer[SUP] 1 [/SUP], Kurtis D Willoughby[SUP] 1 [/SUP], Jimmy Lu[SUP] 3 [/SUP], Elena Arutyunova[SUP] 3 [/SUP], Michael A Joyce[SUP] 4 [/SUP], Holly A Saffran[SUP] 4 [/SUP], Justin A Shields[SUP] 4 [/SUP], Howard S Young[SUP] 2 [/SUP], James A Nieman[SUP] 5 [/SUP], D Lorne Tyrrell[SUP] 4 [/SUP], M Joanne Lemieux[SUP] 3 [/SUP], John C Vederas[SUP] 6 [/SUP]
Affiliations
Abstract
Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (M[SUP]pro[/SUP]) to cleave viral proteins. Consequently, M[SUP]pro[/SUP] 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 M[SUP]pro[/SUP] 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-M[SUP]pro[/SUP] complexes reveal that an alternative binding pocket in M[SUP]pro[/SUP], 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[SUP]+[/SUP] counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for M[SUP]pro[/SUP] inhibitor design.
Keywords: COVID-19; Crystallography; GC376 analogs; Main protease; Protease inhibitor; Structure-guided design.
. 2021 May 30;222:113584.
doi: 10.1016/j.ejmech.2021.113584. Online ahead of print.
Improved SARS-CoV-2 M [SUP]pro[/SUP] inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies
Wayne Vuong[SUP] 1 [/SUP], Conrad Fischer[SUP] 1 [/SUP], Muhammad Bashir Khan[SUP] 2 [/SUP], Marco J van Belkum[SUP] 1 [/SUP], Tess Lamer[SUP] 1 [/SUP], Kurtis D Willoughby[SUP] 1 [/SUP], Jimmy Lu[SUP] 3 [/SUP], Elena Arutyunova[SUP] 3 [/SUP], Michael A Joyce[SUP] 4 [/SUP], Holly A Saffran[SUP] 4 [/SUP], Justin A Shields[SUP] 4 [/SUP], Howard S Young[SUP] 2 [/SUP], James A Nieman[SUP] 5 [/SUP], D Lorne Tyrrell[SUP] 4 [/SUP], M Joanne Lemieux[SUP] 3 [/SUP], John C Vederas[SUP] 6 [/SUP]
Affiliations
- PMID: 34118724
- DOI: 10.1016/j.ejmech.2021.113584
Abstract
Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (M[SUP]pro[/SUP]) to cleave viral proteins. Consequently, M[SUP]pro[/SUP] 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 M[SUP]pro[/SUP] 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-M[SUP]pro[/SUP] complexes reveal that an alternative binding pocket in M[SUP]pro[/SUP], 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[SUP]+[/SUP] counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for M[SUP]pro[/SUP] inhibitor design.
Keywords: COVID-19; Crystallography; GC376 analogs; Main protease; Protease inhibitor; Structure-guided design.