Broad spectrum antiviral BDGR-164 provides protection against lethal neurotropic alphavirus infection in mice

The New World alphaviruses, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and western equine encephalitis virus (WEEV), cause febrile illness that can progress to fatal disease in humans and equids. As there are no therapeutics approved for the treatment of neurotropic alphavirus disease in humans, we report a structurally novel, quinazolinone, BDGR-164, with nanomolar potency against VEEV, EEEV, and WEEV. Using an intranasal route of virus infection in a lethal BALB/c model, to model aerosol infection in a biodefense scenario, prophylactic subcutaneous administration of BDGR-164 conferred 100 % (VEEV), 88 % (EEEV), and 63 % survival (WEEV) compared to uniform lethality in sham-treated animals. Using RNA-Seq and histopathology, we determined that viral RNA levels and antigen were reduced significantly in the brains of mice from the virus-infected, BDGR-164-treated group as compared to virus-infected, sham-treated group. Moreover, there was a significant reduction in the virus-infected, BDGR-164-treated mice in their host immune responses associated with inflammatory signaling, immune cell recruitment, and programmed cell death. Comparison of cytokines in sera from VEEV-, EEEV- or WEEV-infected mice with and without BDGR-164-treatment suggested that lower levels of IL-6, TNF-α, and RANTES levels correlated with protection and may serve as useful early biomarkers in treatment studies in animal models. In conclusion, our studies show broad and potent prophylactic efficacy of BDGR-164 against neurotropic alphaviruses.