Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors.
J Med Chem
; 65(4): 2866-2879, 2022 02 24.
Article
in English
| MEDLINE | ID: covidwho-1440451
ABSTRACT
The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Cysteine Proteinase Inhibitors
/
Benzothiazoles
/
Drug Discovery
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Limits:
Animals
/
Humans
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2022
Document Type:
Article
Affiliation country:
Acs.jmedchem.1c00566
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