Abstract
The search for new drugs against COVID-19 and its causativeagent,SARS-CoV-2, is one of the major trends in the current medicinal chemistry.Targeting capping machinery could be one of the therapeutic conceptsbased on a unique mechanism of action. Viral RNA cap synthesis involvestwo methylation steps, the first of which is mediated by the nsp14protein.
Here, we rationally designed and synthesized a series ofcompounds capable of binding to both the S-adenosyl-l-methionine and the RNA-binding site of SARS-CoV-2 nsp14 N(7)-methyltransferase. These hybrid moleculesshowed excellent potency, high selectivity toward various human methyltransferases,nontoxicity, and high cell permeability.
Despite the outstanding activityagainst the enzyme, our compounds showed poor antiviral performancein vitro. This suggests that the activity of this viral methyltransferasehas no significant effect on virus transcription and replication atthe cellular level.
Therefore, our compounds represent unique toolsto further explore the role of the SARS-CoV-2 nsp14 methyltransferasein the viral life cycle and the pathogenesis of COVID-19.