期刊
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
卷 54, 期 8, 页码 1133-1139出版社
SCIENCE PRESS
DOI: 10.3724/abbs.2022092
关键词
COVID-19; SARS-CoV-2; PLpro; Parthenolide; deISGylation
资金
- National Key Research and Development Program of China [2017YFA0505200]
- Science and Technology Committee of Shanghai [19ZR1428700, 20ZR1430600]
- National Natural Science Foundation of China [82170145, 81700157, 81700475]
- Innovative research team of high-level local universities in Shanghai [SHSMU-ZDCX20211802]
Parthenolide inhibits the activity of SARS-CoV-2 PLpro by covalently binding to specific sites on the protein, thus affecting virus replication. Its mechanism of action involves allosteric regulation to achieve inhibition of PLpro.
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.
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