7LDL

Improved Feline Drugs as SARS-CoV-2 Mpro Inhibitors: Structure-Activity Studies & Micellar Solubilization for Enhanced Bioavailability

Summary for 7LDL

• Entry DOI: 10.2210/pdb7ldl/pdb
• Descriptor: 3C-like proteinase, N-[(2S)-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide (3 entities in total)
• Functional Keywords: covid-19, sars-cov-2, 3clpro, coronavirus, main protease, kinetics, sars, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2, COVID-19 virus)
• Total number of polymer chains: 2
• Total formula weight: 68540.14

Authors

Khan, M.B.,Lu, J.,Arutyunova, E.,Young, H.S.,Lemieux, M.J. (deposition date: 2021-01-13, release date: 2021-07-07, Last modification date: 2024-11-20)

Primary citation

Vuong, W.,Fischer, C.,Khan, M.B.,van Belkum, M.J.,Lamer, T.,Willoughby, K.D.,Lu, J.,Arutyunova, E.,Joyce, M.A.,Saffran, H.A.,Shields, J.A.,Young, H.S.,Nieman, J.A.,Tyrrell, D.L.,Lemieux, M.J.,Vederas, J.C.
Improved SARS-CoV-2 M pro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies.
Eur.J.Med.Chem., 222:113584-113584, 2021

PubMed Abstract: Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (M) to cleave viral proteins. Consequently, M 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 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 complexes reveal that an alternative binding pocket in M, 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 M inhibitor design.

PubMed: 34118724
DOI: 10.1016/j.ejmech.2021.113584

Experimental method

X-RAY DIFFRACTION (2 Å)