Inhibition of Cysteine Proteases via Thiol-Michael Addition Explains the Anti-SARS-CoV‑2 and Bioactive Properties of Arteannuin B

Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SAR...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2023-07, Vol.86 (7), p.1654-1666
Main Authors: Varela, Kaitlyn, Arman, Hadi D., Berger, Mitchel S., Sponsel, Valerie M., Lin, Chin-Hsing Annie, Yoshimoto, Francis K.
Format: Article
Language:English
Subjects:
Artemisinins - chemistry
Caspase 8 - metabolism
COVID-19
Cysteine - pharmacology
Cysteine Proteases - metabolism
Humans
Plant Extracts - chemistry
SARS-CoV-2
Sulfhydryl Compounds - pharmacology
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Summary:Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SARS-CoV-2. In this study, a methyl ester derivative of arteannuin B was isolated when A. annua leaves were extracted with a 1:1 mixture of methanol and dichloromethane. This methyl ester was thought to be formed from the reaction between arteannuin B and the extracting solvent, which was supported by the fact that arteannuin B underwent 1,2-addition when it was dissolved in deuteromethanol. In contrast, in the presence of N-acetylcysteine methyl ester, a 1,4-addition (thiol-Michael reaction) occurred. Arteannuin B hindered the activity of the SARS CoV-2 main protease (nonstructural protein 5, NSP5), a cysteine protease, through time-dependent inhibition. The active site cysteine residue of NSP5 (cysteine-145) formed a covalent bond with arteannuin B as determined by mass spectrometry. In order to determine whether cysteine adduction by arteannuin B can inhibit the development of cancer cells, similar experiments were performed with caspase-8, the cysteine protease enzyme overexpressed in glioblastoma. Time-dependent inhibition and cysteine adduction assays suggested arteannuin B inhibits caspase-8 and adducts to the active site cysteine residue (cysteine-360), respectively. Overall, these results enhance our understanding of how A. annua possesses antiviral and cytotoxic activities.
ISSN:0163-3864
1520-6025
DOI:10.1021/acs.jnatprod.2c01146