Polyphenol rich sugarcane extract restricts select respiratory viruses depending on their mode of entry

We previously showed that Polyphenol rich sugarcane extract (PRSE) displayed significant inhibitory effect against influenza A virus (IAV). In this study, we investigated the mechanism of action (MOA) of PRSE against respiratory viruses in human-derived cells. We showed that PRSE treatment does not promote an antiviral state via expression of interferon stimulated genes (ISGs). We subsequently investigated any potential perturbation on the viral entry process and observed that PRSE treatment did not affect caveolin-mediated endocytosis but led to a significant attenuation in clathrin-mediated endocytosis. We confirmed this inhibitory effect on IAV entry, as infection was unaffected by PRSE when IAV fusion was induced at the plasma membrane, instead of endosomal membranes. Based on these findings we observed significant inhibitory effect of PRSE against respiratory syncytial virus and human metapneumovirus, which utilise clathrin-mediated endocytosis, but not human parainfluenza virus type 3, which fuses at the plasma membrane. In conclusion, we show that PRSE has broad antiviral activity and potentially perturbs virus entry via clathrin-mediated endocytosis to inhibit viral replication in vitro.