3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors.

SARS-CoV-2 nsp14 guanine-7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from -adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14. While the selectivity of 3-(adenosylthio)benzoic acid derivatives against human glycine -methyltransferase was not improved, the discovery of phenyl-substituted analogs may contribute to further development of SARS-CoV-2 nsp14 bisubstrate inhibitors.