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

0574244 - ÚOCHB 2024 RIV US eng J - Journal Article
Štefek, Milan - Chalupská, Dominika - Chalupský, Karel - Zgarbová, Michala - Dvořáková, Alexandra - Krafčíková, Petra - Li, A. S. M. - Šála, Michal - Dejmek, Milan - Otava, Tomáš - Chaloupecká, Ema - Kozák, Jaroslav - Kozic, Ján - Vedadi, M. - Weber, Jan - Mertlíková-Kaiserová, Helena - Nencka, Radim
Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors.
ACS Omega. Roč. 8, č. 30 (2023), s. 27410-27418. ISSN 2470-1343. E-ISSN 2470-1343
R&D Projects: GA MZd(CZ) NU20-05-00472; GA MŠMT(CZ) LX22NPO5103
Institutional support: RVO:61388963
Keywords : SARS-CoV-2 * genetics * inhibitors
OECD category: Virology
Impact factor: 4.1, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acsomega.3c02815

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.
Permanent Link: https://hdl.handle.net/11104/0344580