•  Bisubstrates as mimics of RNA 2′-O-methylation transition state with SAM.
•  16 dinucleosides with two adenosines joined by various nitrogen-containing linkers.
•  Bisubstrate compounds were barely active against viral 2′-O-methyltransferases.
•  Discovery of a potent and specific inhibitor of SARS-CoV nsp14 N7-methyltransferase.
•  Molecular docking and biophysical assays corroborated observed SAR.