Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00574244" target="_blank" >RIV/61388963:_____/23:00574244 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11310/23:10467206 RIV/60461373:22330/23:43926872
Result on the web
<a href="https://doi.org/10.1021/acsomega.3c02815" target="_blank" >https://doi.org/10.1021/acsomega.3c02815</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acsomega.3c02815" target="_blank" >10.1021/acsomega.3c02815</a>

Result language
angličtina
Original language name
Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors
Original language description
The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the S-adenosyl-l-methionine and the RNA-binding site of SARS-CoV-2 nsp14 N7-methyltransferase. These hybrid molecules showed excellent potency, high selectivity toward various human methyltransferases, nontoxicity, and high cell permeability. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase has no significant effect on virus transcription and replication at the cellular level. Therefore, our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in the viral life cycle and the pathogenesis of COVID-19.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10607 - Virology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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