2. Academic Validation
  3. Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors

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

  • ACS Omega. 2023 Jul 21;8(30):27410-27418. doi: 10.1021/acsomega.3c02815.
Milan Štefek 1 2,  Dominika Chalupská 1,  Karel Chalupský 1,  Michala Zgarbová 1,  Alexandra Dvořáková 1,  Petra Krafčíková 1,  Alice Shi Ming Li 3,  Michal Šála 1,  Milan Dejmek 1,  Tomáš Otava 1,  Ema Chaloupecká 1,  Jaroslav Kozák 1,  Ján Kozic 1,  Masoud Vedadi 3 4,  Jan Weber 1,  Helena Mertlíková-Kaiserová 1,  Radim Nencka 1
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 6 166 10, Czech Republic.
  • 2 Department of Organic Chemistry, Faculty of Science, Charles University, Prague 128 00, Czech Republic.
  • 3 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 4 QBI COVID-19 Research Group (QCRG), San Francisco, California 94158, United States.
PMID: 37546609 DOI: 10.1021/acsomega.3c02815
Abstract

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.

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