Rational design of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors

The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in current medicinal chemistry. Targeting capping machinery could be one of 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 7-N methyltransferase. These hybrid molecules exerted excellent potency, high selectivity towards various human methyltransferases, they are nontoxic and highly cell permeable. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase is mainly associated with immune response. Our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in viral replication.