| Autor: |
Raitis Bobrovs, Iveta Kanepe, Nauris Narvaiss, Liene Patetko, Gints Kalnins, Mihails Sisovs, Anna L. Bula, Solveiga Grinberga, Martins Boroduskis, Anna Ramata-Stunda, Nils Rostoks, Aigars Jirgensons, Kaspars Tars, Kristaps Jaudzems |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Pharmaceuticals, Vol 14, Iss 12, p 1243 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
1424-8247 |
| DOI: |
10.3390/ph14121243 |
| Popis: |
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC50 < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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