Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase.
Jung E, Soto-Acosta R, Xie J, Wilson DJ, Dreis CD, Majima R, Edwards TC, Geraghty RJ, Chen L.
Taking advantage of the uniquely constricted active site of SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with the SAM and RNA substrate binding pockets. Our efforts have led to nanomolar inhibitors including compounds <b>3</b> and <b>10</b>. As a prototypic inhibitor, compound <b>3</b> also has an excellent selectivity profile over a panel of human methyltransferases. Remarkably, <i>C</i>-nucleoside <b>10</b> exhibits high antiviral activity and low cytotoxicity, leading to a therapeutic index (CC<sub>50</sub>/EC<sub>50</sub>) greater than 139. Furthermore, a brief metabolic profiling of these two compounds suggests that they are less likely to suffer from major metabolic liabilities. Moreover, computational docking studies point to protein-ligand interactions that can be exploited to enhance inhibitory activity. In short, discovery of inhibitor <b>10</b> clearly demonstrates that potent and selective anti-SARS-CoV-2 activity can be achieved by targeting the Nsp14 methyltransferase. Therefore, the current work strongly supports the continued pursuit of Nsp14 methyltransferase inhibitors as COVID-19 therapeutics.