Abstract
The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II, and XII, with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, 23R (Jun8-76-3A) that is structurally distinct from the canonical Mpro inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 Mpro with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Antiviral Agents / chemical synthesis
-
Antiviral Agents / chemistry
-
Antiviral Agents / pharmacology*
-
COVID-19 / metabolism
-
COVID-19 Drug Treatment
-
Chlorocebus aethiops
-
Coronavirus 3C Proteases / antagonists & inhibitors*
-
Coronavirus 3C Proteases / isolation & purification
-
Coronavirus 3C Proteases / metabolism
-
Cysteine Proteinase Inhibitors / chemical synthesis
-
Cysteine Proteinase Inhibitors / chemistry
-
Cysteine Proteinase Inhibitors / pharmacology*
-
Dose-Response Relationship, Drug
-
Drug Design*
-
Humans
-
Microbial Sensitivity Tests
-
Models, Molecular
-
Molecular Structure
-
Proline / analogs & derivatives
-
Proline / chemical synthesis
-
Proline / chemistry
-
Proline / pharmacology
-
Pyrrolidines / chemical synthesis
-
Pyrrolidines / chemistry
-
Pyrrolidines / pharmacology
-
SARS-CoV-2 / drug effects*
-
SARS-CoV-2 / enzymology
-
Sulfonic Acids / chemical synthesis
-
Sulfonic Acids / chemistry
-
Sulfonic Acids / pharmacology
-
Vero Cells
Substances
-
Antiviral Agents
-
Cysteine Proteinase Inhibitors
-
Pyrrolidines
-
Sulfonic Acids
-
N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
-
Proline
-
3C-like proteinase, SARS-CoV-2
-
Coronavirus 3C Proteases
-
GC376