High-Throughput Screening for Inhibitors of the SARS-CoV-2 Protease Using a FRET-Biosensor.
Molecules
; 25(20)2020 Oct 13.
Article
in English
| MEDLINE | ID: covidwho-1197552
ABSTRACT
The global SARS-CoV-2 pandemic started late 2019 and currently continues unabated. The lag-time for developing vaccines means it is of paramount importance to be able to quickly develop and repurpose therapeutic drugs. Protein-based biosensors allow screening to be performed using routine molecular laboratory equipment without a need for expensive chemical reagents. Here we present a biosensor for the 3-chymotrypsin-like cysteine protease from SARS-CoV-2, comprising a FRET-capable pair of fluorescent proteins held in proximity by a protease cleavable linker. We demonstrate the utility of this biosensor for inhibitor discovery by screening 1280 compounds from the Library of Pharmaceutically Active Compounds collection. The screening identified 65 inhibitors, with the 20 most active exhibiting sub-micromolar inhibition of 3CLpro in follow-up EC50 assays. The top hits included several compounds not previously identified as 3CLpro inhibitors, in particular five members of a family of aporphine alkaloids that offer promise as new antiviral drug leads.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Pneumonia, Viral
/
Protease Inhibitors
/
Biosensing Techniques
/
Viral Nonstructural Proteins
/
Coronavirus Infections
/
Fluorescence Resonance Energy Transfer
/
Betacoronavirus
Type of study:
Cohort study
/
Prognostic study
Topics:
Vaccines
Limits:
Humans
Language:
English
Journal subject:
Biology
Year:
2020
Document Type:
Article
Affiliation country:
Molecules25204666
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