SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model.
Science
; 371(6536): 1374-1378, 2021 03 26.
Article
in English
| MEDLINE | ID: covidwho-1255508
ABSTRACT
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Protease Inhibitors
/
Coronavirus 3C Proteases
/
COVID-19 Drug Treatment
Type of study:
Prognostic study
Limits:
Animals
/
Humans
Language:
English
Journal:
Science
Year:
2021
Document Type:
Article
Affiliation country:
SCIENCE.ABF1611
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