Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening

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 agent...

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Published in:Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 12; p. 1243
Main Authors: Bobrovs, Raitis, Kanepe, Iveta, Narvaiss, Nauris, Patetko, Liene, Kalnins, Gints, Sisovs, Mihails, Bula, Anna L., Grinberga, Solveiga, Boroduskis, Martins, Ramata-Stunda, Anna, Rostoks, Nils, Jirgensons, Aigars, Tars, Kaspars, Jaudzems, Kristaps
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 30.11.2021
MDPI
Subjects:
Amino acids
antiviral drugs
Binding sites
Coronaviruses
COVID-19
Enzymes
Epidemics
high-throughput virtual screening
Hydrogen bonds
Immune system
Ligands
Middle East respiratory syndrome
MTase inhibitors
nsp14
nsp16
Respiratory diseases
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
antiviral drugs
SARS-CoV-2
nsp14
high-throughput virtual screening
MTase inhibitors
nsp16
ISSN:1424-8247, 1424-8247
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Summary: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.
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ISSN:1424-8247
1424-8247
DOI:10.3390/ph14121243