Theoretical investigating mechanisms of drug-resistance generated by mutation-induced changes in influenza viruses

Influenza A (A/HxNy) is a significant public health concern due to its high infectiousness and mortality. Neuraminidase, which interacts with sialic acid (SIA) in host cells, has become an essential target since its highly conserved catalytic center structure, while resistance mutations have already generated. Here, a detailed investigation of the drug resistance mechanism caused by mutations was performed for subtype N9 (A/H7N9). Molecular dynamics simulation and alanine-scanning-interaction-entropy method (ASIE) were used to explore the critical differences between N9 and Zanamivir (ZMR) before and after R294K mutation. The results showed that the mutation caused the hydrogen bond between Arg294 and ZMR to break, then the hydrogen bonding network was disrupted, leading to weakened binding ability and resistance. While in wild type (A/H7N9(WT)), this hydrogen bond was initially stable. Mean-while, N9 derived from A/H11N9 was obtained as an R292K mutation. Then the relative binding free energy of N9 with five inhibitors (SIA, DAN, ZMR, G28, and G39) was predicted, basically consistent with experimental values, indicating that the calculated results were reliable by ASIE. In addition, Arg292 and Tyr406 were hot spots in the A/H11N9(WT)-drugs. However, Lys292 was not observed as a favorable contributing residue in A/H11N9(R292K), which may promote resistance. In comparison, Tyr406 remained the hotspot feature when SIA, ZMR, and G28 binding to A/H11N9(R292K). Combining the two groups, we speculate that the resistance was mainly caused by the disruption of the hydrogen bonding network and the transformation of hotspots. This study could guide novel drug delivery of drug-resistant mutations in the treatment of A/HxN9.

Automated summary

The study investigated the drug resistance mechanism caused by mutations in subtype N9 (A/H7N9) of Influenza A, revealing that the mutation led to the disruption of the hydrogen bonding network, weakening the drug binding ability and potentially promoting resistance. This study could provide insights for the development of novel drug delivery strategies in treating A/HxN9 with drug-resistant mutations.