Identification of Natural Products Inhibiting SARS-CoV-2 by Targeting Viral Proteases : A Combined in Silico and in Vitro Approach
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 (Mpro) and papain-like protease (PLpro), 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 Mpro by more than 60% at a concentration of 20 μM, and four of them with high potency (IC50 < 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 IC50 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 Mpro 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:86 |
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| Enthalten in: |
Journal of natural products - 86(2023), 2 vom: 24. Feb., Seite 264-275 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wasilewicz, Andreas [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 27.02.2023 Date Revised 03.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jnatprod.2c00843 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM351624503 |
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| 100 | 1 | |a Wasilewicz, Andreas |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of Natural Products Inhibiting SARS-CoV-2 by Targeting Viral Proteases |b A Combined in Silico and in Vitro Approach |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 (Mpro) and papain-like protease (PLpro), 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 Mpro by more than 60% at a concentration of 20 μM, and four of them with high potency (IC50 < 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 IC50 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 Mpro 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Viral Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 650 | 7 | |a Peptide Hydrolases |2 NLM | |
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| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Biological Products |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 700 | 1 | |a Kirchweger, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Bojkova, Denisa |e verfasserin |4 aut | |
| 700 | 1 | |a Abi Saad, Marie Jose |e verfasserin |4 aut | |
| 700 | 1 | |a Langeder, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Bütikofer, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Adelsberger, Sigrid |e verfasserin |4 aut | |
| 700 | 1 | |a Grienke, Ulrike |e verfasserin |4 aut | |
| 700 | 1 | |a Cinatl, Jindrich |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Petermann, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Scapozza, Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Orts, Julien |e verfasserin |4 aut | |
| 700 | 1 | |a Kirchmair, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Rabenau, Holger F |e verfasserin |4 aut | |
| 700 | 1 | |a Rollinger, Judith M |e verfasserin |4 aut | |
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