Effect of antivirals in NPCs derived from induced pluripotent stem cells

Neurotropic viral infections of the central nervous system (CNS) cause a broad spectrum of clinical manifestations, which include neuropathological changes and subsequent neurological conditions. Currently utilized antiviral drugs are targeted towards specific viruses or members of a specific family. However, the recent COVID-19 pandemic caused by the neurotropic virus SARS-CoV-2 has highlighted the importance of having broad spectrum agents available in our armamentarium that can limit replication of emerging and reemerging neurotropic viruses and future unidentified pathogens that can pose a risk for the next pandemic. Neural progenitor cells (NPCs) were derived from hiPSC-neurons as previously described (D’Aiuto et al. Organogenesis. 2014;10(4):365-77). Using a human induced pluripotent stem cells (hiPSCs)-based neuronal platform, we have identified a small molecule termed "R430", a lycorane-type alkaloid which is able to inhibit productive (lytic) HSV-1 infections in vitro and in a murine model of HSV-1 infection. Importantly, later experiments showed that R430 exhibits potency against other DNA viruses (HSV-1, HCMV, HBV, HCV), as well as RNA viruses (ZIKV strains FSS-13025 and PE-243). However, higher toxicity when compared to acyclovir (the gold standard drug for herpes infections) was observed in fibroblasts and hepatocytes. Thus, we employed a structure-activity relationship (SAR) study to generate new R430 analogs which would possess a comparable antiviral activity but a reduced cell toxicity.