Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay.
Commun Biol
; 5(1): 169, 2022 02 25.
Article
in English
| MEDLINE | ID: covidwho-1713217
ABSTRACT
SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Drug Evaluation, Preclinical
/
Viral Protease Inhibitors
/
Coronavirus 3C Proteases
/
Coronavirus Papain-Like Proteases
/
SARS-CoV-2
Type of study:
Prognostic study
Topics:
Traditional medicine
/
Variants
Limits:
Humans
Language:
English
Journal:
Commun Biol
Year:
2022
Document Type:
Article
Affiliation country:
S42003-022-03090-9
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