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

摘要

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.