AZT acts as an anti-influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/H1N1 RNA dependent RNA polymerase

To develop potent drugs that inhibit the activity of influenza virus RNA dependent RNA polymerase (RdRp), a set of compounds favipiravir, T-705, T-1105 and T-1106, ribavirin, ribavirin triphosphate viramidine, 2FdGTP (2-deoxy-2-fluoroguanosine triphosphate) and AZT-TP (3-Azido-3-deoxy-thymidine-5-triphosphate) were docked with a homology model of IAV RdRp from the A/PR/8/34/H1N1 strain. These compounds bind to four pockets A-D of the IAV RdRp with different mechanism of action. In addition, AZT-TP also binds to the PB1 catalytic site near to the tip of the priming loop with a highest G of -16.7Kcal/mol exhibiting an IC50 of 1.12 mu M in an in vitro enzyme transcription assay. This shows that AZT-TP mainly prevents the incorporation of incoming nucleotide involved in initiation of vRNA replication. Conversely, 2FdGTP used as a positive control binds to pocket-B at the end of tunnel-II with a highest G of -16.3Kcal/mol inhibiting chain termination with a similar IC50 of 1.12 mu M. Overall, our computational results in correlation with experimental studies gives information for the first time about the binding modes of the known influenza antiviral compounds in different models of vRNA replication by IAV RdRp. This in turn gives new structural insights for the development of new therapeutics exhibiting high specificity to the PB1 catalytic site of influenza A viruses.