Potential use of c-Myc inhibitors as anti-viral agents against Influenza A virus

Influenza A viruses (IAVs) are the etiological agent responsible for influenza, a common respiratory illness in humans. It is a global health threat and economic burden to humanity considering influenza related hospitalizations, potential pandemic outbreaks and zoonotic potential of the virus. Hence, it is necessary to better understand the biology of IAV in aim to identify novel drug targets against influenza. Recently, Smallwood et al. reported that IAV infection causes metabolic reprogramming of host cells through a host protein named c-Myc. c-Myc is a well-characterized transcription factor that activates expression of various genes involved in cellular proliferation, cellular metabolism, protein biosynthesis, and apoptosis. Although being extensively studied in cancer biology, c-Myc was only recently recognized in context of IAV biology. Yet, importance of Myc pathway for complete life cycle of IAV has been ill-defined. In my initial observations, 10074-G5, a small molecule inhibitor of c-Myc, significantly delayed viral protein expression in lung epithelial cell lines, i.e. A549 cells. Drug treatment had only minor effect on responsiveness of cells to infection, ex. IFNß expression, whereas replication of virus was severely impeded. Moreover, A549 showed greatly decreased viral propagation in presence of 10074-G5. On the other hand, we found that transcript levels of c-Myc, as well as c-Myc target genes, were elevated in mouse lungs upon infection with pandemic IAV strain pH1N1 and avian IAV strain H5N1. This increase was as rapid as 12-hour post-infection and sustained through at least the first 4 days of infection, if not more. Interestingly, in a pilot experiment, 10074-G5 treatment led to a small but significant decrease in viral lung titers in mice, thus partially confirming the importance of Myc pathway for IAV replication cycle in vivo. Thus, I speculate that commercially available drugs designed to inhibit c-Myc activity may be used to understand the importance of c-Myc for IAV biology and possibly re-purposed as potential anti-viral agents against IAV. Considering the highly diverse functions attributed to this pathway, I am convinced that it is of interest to the field that we thoroughly understand molecular importance of c-Myc for IAV biology.