Gemcitabine Inhibits Poliovirus Replication and Interferes with Viral RNA Elongation
thesisposted on 19.10.2016, 00:00 by Zhuoran Zhang
While we are approaching the end game of global eradication of circulating wild-type polioviruses(PV), vaccination with oral poliovirus vaccine (OPV) has led to emergence of circulating vaccine-derived poliovirus (cVDPV) and vaccine-associated paralytic poliomyelitis (VAPP). Complete cessation of all poliovirus infections may require stopping use of OPV and formulating improved vaccines and new antiviral drugs. Currently, no licensed drugs are available to treat chronically infected poliovirus excreters. Here, we created a modified PV expressing Gaussia Luciferase (PV-GLuc) and developed a cell-based high-throughput screening (HTS) antiviral assay. Using the validated HTS assay, we screened the FDA-approved drug library of compounds and identified candidate agents capable of inhibiting PV replication. We then characterized anti-poliovirus activity for the best hit, Gemcitabine, a nucleoside analogue used in tumor chemotherapy. We found that Gemcitabine inhibited PV Mahoney replication with IC50 of 0.3μM. It completely protected HeLa cells from PV-induced cytopathic effects at 5μM, without detectable toxicity for cell viability. Furthermore, Gemcitabine metabolite directly inhibited the ability of PV RNA polymerase to synthesize or elongate PV RNA. Since PV RNA polymerase is somehow conserved among species in Picornaviridae family, Gemcitabine may be further developed as an attractive broad-spectrum antiviral for PV and others.