Known drug induces nucleoporins Rae1/ mrnp41 and Nup98: A paradigm shift in VSV oncolytic virus modulation

Viral infections persistently threaten human health. Development of broad-range antiviral drugs capable of enhancing cellular innate immunity could potentially avoid future pandemics. Similarly, cancer is a major health concern and leading cause of death worldwide. Innovative therapeutic approaches, such as the use of oncolytic viruses, are worth exploring. Such therapy requires drugs that would minimize viral infectivity to normal cells and/or enhance viral oncolytic potency. Drug “A” (concealed due to patent) is known to exert effects that include cancer-cell killing and inhibition of viruses such as HIV, HCV, polio and influenza A. Strikingly, viruses that are affected by Drug A have two mechanisms in common: blockage of the antiviral STAT1 pathway and take-over of cellular Nuclear Pore Complex (NPC) function. Vesicular stomatitis virus (VSV) is the prototype virus for take-over of NPC function via blockage of mRNA export.
In this study, we investigated the effects of Drug A on the expression of nucleoporins Nup98 and Rae1/mrnp41, as well as on the infection/replication of oncolytic VSV. Here, we show for the first time that Drug A up-regulates both Nup98 and Rae1 in a concentration-dependent and STAT1-dependent manner. Drug A also exerts biphasic effects on VSV protein expression and replication. Low concentrations of Drug A (0.125µM) increase VSV protein levels and viral titers, while higher concentrations (0.25-2.0µM) decrease viral protein levels and titers. Our findings lay the foundation for repositioning of Drug A as an oncolytic virotherapy neoadjuvant.