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Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors
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SYSNO ASEP 0574244 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors Author(s) Štefek, Milan (UOCHB-X)
Chalupská, Dominika (UOCHB-X) ORCID
Chalupský, Karel (UOCHB-X)
Zgarbová, Michala (UOCHB-X)
Dvořáková, Alexandra (UOCHB-X)
Krafčíková, Petra (UOCHB-X) ORCID
Li, A. S. M. (CA)
Šála, Michal (UOCHB-X) RID, ORCID
Dejmek, Milan (UOCHB-X) RID, ORCID
Otava, Tomáš (UOCHB-X) ORCID
Chaloupecká, Ema (UOCHB-X) ORCID
Kozák, Jaroslav (UOCHB-X) RID, ORCID
Kozic, Ján (UOCHB-X) ORCID
Vedadi, M. (CA)
Weber, Jan (UOCHB-X) RID, ORCID
Mertlíková-Kaiserová, Helena (UOCHB-X) RID, ORCID
Nencka, Radim (UOCHB-X) RID, ORCIDSource Title ACS Omega. - : American Chemical Society - ISSN 2470-1343
Roč. 8, č. 30 (2023), s. 27410-27418Number of pages 9 s. Language eng - English Country US - United States Keywords SARS-CoV-2 ; genetics ; inhibitors OECD category Virology R&D Projects NU20-05-00472 GA MZd - Ministry of Health (MZ) LX22NPO5103 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 001031748300001 EID SCOPUS 85166762149 DOI 10.1021/acsomega.3c02815 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1021/acsomega.3c02815
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