Parthenolide reveals an allosteric mode to inhibit the deISGylation activity of SARS-CoV2 papain-like protease.
Acta Biochim Biophys Sin (Shanghai)
; 54(8): 1133-1139, 2022 Aug 25.
Article
in English
| MEDLINE | ID: covidwho-2289200
ABSTRACT
The coronavirus papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15 (ISG15), which enable it to participate in virus replication and host innate immune pathways. Therefore, PLpro is considered an attractive antiviral drug target. Here, we show that parthenolide, a germacrane sesquiterpene lactone, has SARS-CoV-2 PLpro inhibitory activity. Parthenolide covalently binds to Cys-191 or Cys-194 of the PLpro protein, but not the Cys-111 at the PLpro catalytic site. Mutation of Cys-191 or Cys-194 reduces the activity of PLpro. Molecular docking studies show that parthenolide may also form hydrogen bonds with Lys-192, Thr-193, and Gln-231. Furthermore, parthenolide inhibits the deISGylation but not the deubiquitinating activity of PLpro in vitro. These results reveal that parthenolide inhibits PLpro activity by allosteric regulation.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Coronavirus Papain-Like Proteases
/
COVID-19 Drug Treatment
Limits:
Humans
Language:
English
Journal:
Acta Biochim Biophys Sin (Shanghai)
Journal subject:
Biophysics
/
Biochemistry
Year:
2022
Document Type:
Article
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