Development of anti-Yellow Fever agents in vitro and in mice

Project Summary/Abstract Yellow fever virus (YFV) is a vector borne Flavivirus which is categorized under category B as a priority emerging pathogen by NIAID in conjunction with the U.S Department of Homeland Security (DHS) and the Center for Disease Control (CDC). Despite the availability of a vaccine, YFV continues to be a significant public health threat with recent outbreaks in Brazil and some African countries. Therefore, development of antiviral agents remains highly pertinent. The major goal of our proposal is to develop potent antiviral candidate(s) for YFV. We recently identified several lead compounds from our nucleoside analog library with sub-micromolar anti-YFV activity in Huh-7 cells. Our research plan includes two Specific Aims: 1) Chemical optimization and determination of antiviral activity and toxicity profiles of lead compounds for inhibition of YFV infection in relevant novel biological systems; and 2) To determine the stability, pharmacokinetics and in vivo efficacy of the lead compound(s) for antiviral activity against YFV in a relevant mouse model. Selection for drug resistant viruses will also be performed and confirmed by site directed mutagenesis. Results from these preclinical studies will help identify potential clinical candidate(s) for treatment of YFV infection in humans.