Potent Inhibition of SARS-CoV-2 nsp14 N7-Methyltransferase bySulfonamide-Based Bisubstrate Analogues

Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs,and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the designand synthesis of nucleoside-derived inhibitors against the SARS-CoV-2 nsp14 (N7-guanine)-methyltransferase (N7-MTase) thatcatalyzes the transfer of the methyl group from theS-adenosyl-L-methionine (SAM) cofactor to theN7-guanosine cap. Sevencompounds out of 39 SAM analogues showed remarkable double-digit nanomolar inhibitory activity against theN7-MTase nsp14.Molecular docking supported the structure-activity relationships of these inhibitors and a bisubstrate-based mechanism of action.The three most potent inhibitors significantly stabilized nsp14 (Delta Tm approximate to 11 degrees C), and the best inhibitor demonstrated high selectivityfor nsp14 over human RNAN7-MTase.

Automated summary

This study focuses on the design and synthesis of inhibitors against SARS-CoV-2 enzymes involved in RNA capping, which are important for viral RNA stability, mRNA translation, and evasion of innate immunity. Seven compounds showed significant inhibitory activity, and the three most potent inhibitors stabilized the enzyme effectively.