Sulforaphane is a reversible covalent inhibitor of 3‐chymotrypsin‐like protease of SARS‐CoV‐2
Zinuo Chen, Ruikun Du, Laura Cooper, Jazmin Galván Achi, Meiyue Dong, Yan Ran, Jiwei Zhang, Peng Zhan, Lijun Rong, Qinghua Cui
Abstract
Abstract The ongoing pandemic of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has posed a major public health threat worldwide and emphasizes an urgent need for effective therapeutics. Recently, Ordonez et al. identified sulforaphane (SFN) as a novel coronavirus inhibitor both in vitro and in mice, but the mechanism of action remains elusive. In this study, we independently discovered SFN for its inhibitory effect against SARS‐CoV‐2 using a target‐based screening approach, identifying the viral 3‐chymotrypsin‐like protease (3CL pro ) as a target of SFN. Mechanistically, SFN inhibits 3CL pro in a reversible, mixed‐type manner. Moreover, enzymatic kinetics studies reveal that SFN is a slow‐binding inhibitor, following a two‐step interaction. Initially, an encounter complex forms by specific binding of SFN to the active pocket of 3CL pro ; subsequently, the isothiocyanate group of SFN as “warhead” reacts covalently to the catalytic cysteine in a slower velocity, stabilizing the SFN‐3CL pro complex. Our study has identified a new lead of the covalent 3CL pro inhibitors which has potential to be developed as a therapeutic agent to treat SARS‐CoV‐2 infection.