Identification of Natural Products Inhibiting SARS-CoV-2 by Targeting Viral Proteases
- Author(s)
- Andreas Wasilewicz, Benjamin Kirchweger, Denisa Bojkova, Marie Jose Abi Saad, Julia Langeder, Matthias Butikofer, Sigrid Adelsberger, Ulrike Grienke, Jindrich Cinatl Jr, Olivier Petermann, Leonardo Scapozza, Julien Orts, Johannes Kirchmair, Holger F. Rabenau, Judith M. Rollinger
- Abstract
In this study, an integrated in silico-in vitro approach was employed to discover natural products (NPs) active against SARS-CoV-2. The two SARS-CoV-2 viral proteases, i.e., main protease (M
pro) and papain-like protease (PL
pro), were selected as targets for the in silico study. Virtual hits were obtained by docking more than 140,000 NPs and NP derivatives available in-house and from commercial sources, and 38 virtual hits were experimentally validated in vitro using two enzyme-based assays. Five inhibited the enzyme activity of SARS-CoV-2 M
pro by more than 60% at a concentration of 20 μM, and four of them with high potency (IC
50 < 10 μM). These hit compounds were further evaluated for their antiviral activity against SARS-CoV-2 in Calu-3 cells. The results from the cell-based assay revealed three mulberry Diels-Alder-type adducts (MDAAs) from Morus alba with pronounced anti-SARS-CoV-2 activities. Sanggenons C (12), O (13), and G (15) showed IC
50 values of 4.6, 8.0, and 7.6 μM and selectivity index values of 5.1, 3.1 and 6.5, respectively. The docking poses of MDAAs in SARS-CoV-2 M
pro proposed a butterfly-shaped binding conformation, which was supported by the results of saturation transfer difference NMR experiments and competitive
1H relaxation dispersion NMR spectroscopy.
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Eidgenössische Technische Hochschule Zürich, Geneva University Hospital, University Hospital Frankfurt, Johann Wolfgang Goethe-Universität Frankfurt am Main
- Journal
- Journal of Natural Products
- Volume
- 86
- Pages
- 264-275
- No. of pages
- 12
- ISSN
- 0163-3864
- DOI
- https://doi.org/10.1021/acs.jnatprod.2c00843
- Publication date
- 01-2023
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 102004 Bioinformatics, 301207 Pharmaceutical chemistry, 301204 Pharmacognosy
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Analytical Chemistry, Molecular Medicine, Complementary and alternative medicine, Pharmacology, Pharmaceutical Science, Organic Chemistry
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/identification-of-natural-products-inhibiting-sarscov2-by-targeting-viral-proteases(607dcfea-8562-4d3f-bf10-5b95e1d4e6b4).html