Validation and Invalidation of SARS-CoV-2 Papain-like Protease Inhibitors.
ACS Pharmacol Transl Sci
; 5(2): 102-109, 2022 Feb 11.
Article
in English
| MEDLINE | ID: covidwho-1947212
ABSTRACT
SARS-CoV-2 encodes two viral cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), both of which are validated antiviral drug targets. PLpro is involved in the cleavage of viral polyproteins as well as immune modulation by removing ubiquitin and interferon-stimulated gene product 15 (ISG15) from host proteins. Therefore, targeting PLpro might be a two-pronged approach. Several compounds including YM155, cryptotanshinone, tanshinone I, dihydrotanshinone I, tanshinone IIA, SJB2-043, 6-thioguanine, and 6-mercaptopurine were recently identified as SARS-CoV-2 PLpro inhibitors through high-throughput screenings. In this study, we aim to validate/invalidate the reported PLpro inhibitors using a combination of PLpro target-specific assays including enzymatic FRET assay, thermal shift binding assay (TSA), and cell-based FlipGFP assay. Collectively, our results showed that all compounds tested either did not show binding or led to denaturation of PLpro in the TSA binding assay, which might explain their weak enzymatic inhibition in the FRET assay. In addition, none of the compounds showed cellular PLpro inhibition as revealed by the FlipGFP assay. Therefore, more efforts are needed to search for potent and specific SARS-CoV-2 PLpro inhibitors.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Prognostic study
Language:
English
Journal:
ACS Pharmacol Transl Sci
Year:
2022
Document Type:
Article
Affiliation country:
Acsptsci.1c00240
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