tetano
Editor, Senior Moderator
J Med Virol
. 2023 Feb 24.
doi: 10.1002/jmv.28609. Online ahead of print.
Sulforaphane is a reversible covalent inhibitor of 3-chymotrypsin-like protease of SARS-CoV-2
Zinuo Chen[SUP] 1 [/SUP], Ruikun Du[SUP] 1 2 [/SUP], Laura Cooper[SUP] 3 [/SUP], Jazmin Galvan Achi[SUP] 3 [/SUP], Meiyue Dong[SUP] 1 [/SUP], Yan Ran[SUP] 1 [/SUP], Jiwei Zhang[SUP] 4 [/SUP], Peng Zhan[SUP] 4 [/SUP], Lijun Rong[SUP] 3 [/SUP], Qinghua Cui[SUP] 1 2 [/SUP]
Affiliations
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[SUP]pro[/SUP] ) as a target of SFN. Mechanistically, SFN inhibits 3CL[SUP]pro[/SUP] 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[SUP]pro[/SUP] ; subsequently, the isothiocyanate group of SFN as "warhead" reacts covalently to the catalytic cysteine in a slower velocity, stabilizing the SFN-3CL[SUP]pro[/SUP] complex. Our study has identified a new lead of the covalent 3CL[SUP]pro[/SUP] inhibitors which has potential to be developed as a therapeutic agent to treat SARS-CoV-2 infection. This article is protected by copyright. All rights reserved.
Keywords: 3-chymotrypsin-like protease; Covalent inhibitor; SARS-CoV-2; Sulforaphane.
. 2023 Feb 24.
doi: 10.1002/jmv.28609. Online ahead of print.
Sulforaphane is a reversible covalent inhibitor of 3-chymotrypsin-like protease of SARS-CoV-2
Zinuo Chen[SUP] 1 [/SUP], Ruikun Du[SUP] 1 2 [/SUP], Laura Cooper[SUP] 3 [/SUP], Jazmin Galvan Achi[SUP] 3 [/SUP], Meiyue Dong[SUP] 1 [/SUP], Yan Ran[SUP] 1 [/SUP], Jiwei Zhang[SUP] 4 [/SUP], Peng Zhan[SUP] 4 [/SUP], Lijun Rong[SUP] 3 [/SUP], Qinghua Cui[SUP] 1 2 [/SUP]
Affiliations
- PMID: 36840402
- DOI: 10.1002/jmv.28609
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[SUP]pro[/SUP] ) as a target of SFN. Mechanistically, SFN inhibits 3CL[SUP]pro[/SUP] 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[SUP]pro[/SUP] ; subsequently, the isothiocyanate group of SFN as "warhead" reacts covalently to the catalytic cysteine in a slower velocity, stabilizing the SFN-3CL[SUP]pro[/SUP] complex. Our study has identified a new lead of the covalent 3CL[SUP]pro[/SUP] inhibitors which has potential to be developed as a therapeutic agent to treat SARS-CoV-2 infection. This article is protected by copyright. All rights reserved.
Keywords: 3-chymotrypsin-like protease; Covalent inhibitor; SARS-CoV-2; Sulforaphane.