The current study provides the first biochemical evidence that MPA can directly interact with an RNA guanylyltransferase and inhibit its activity. We demonstrated that MPA inhibits the RNA guanylyltransferase reaction by preventing the catalytic transfer of the GMP moiety onto an acceptor RNA. Moreover, our RNA binding studies demonstrated that the binding of the enzyme-GMP intermediate to RNA is inhibited in the presence of MPA. As such, MPA represents a novel type of inhibitor against RNA guanylyltransferases that inhibits the second step of the catalytic reaction. Several inhibitors of the RNA guanylyltransferase activity have previously been identified [60] . However, these inhibitors all target the formation of the enzyme-GMP complex. For instance, foscarnet inhibits the formation of the enzyme-GMP intermediate on account of its analogous nature to pyrophosphate (PPi), a product of the RNA guanylyltransferase reaction [24] . Ribavirin, a broad-spectrum nucleoside analogue used as an antiviral for severe respiratory syncytial virus, Hepatitis C and other viral infections, is another example of an RNA guanylyltransferase inhibitor that prevents the formation of the enzyme-GMP intermediate [25] . Non-nucleoside competitive inhibitors have also been generated against the RNA guanylyltransferase of respiratory syncitial virus [61] . MPA, with its ability to inhibit the second step of the RNA guanylyltransferase reaction, has the potential to serve as a template for the development of more potent inhibitors. In fact, a number of MPA derivatives have been developed in recent years [62, 63] . Analysis of the interaction between these derivatives and RNA guanylyltransferases could shed light on the chemistry of the RNA capping reaction and lead to the development of more efficient anti-proliferative/antimicrobial drugs.