Exploiting Common Replication Steps to Discover and Develop Broad Spectrum Inhibitors of Flaviviruses

Flaviviruses, including dengue virus (DENV), Hepatitis C Virus (HCV), West Nile virus (WNV) and yellow fever virus (YFV), cause human disease on a global scale. Currently, there are no antiviral therapies for infection with these viruses or for other emerging members of the flavivirus family (Japanese Encephalitis, St. Louis Encephalitis and Tick-Borne Encephalitis for example). In this project, we will pursue a comprehensive strategy to develop broad spectrum antiviral drugs that may be effective against two or more flaviviruses.

Key targets are DENV and WNV. Three unique steps/targets in flavivirus replication will be pursued: virus entry, 3’ stem-loop in the antigenome, and viral protease NS2B-NS3. Drug targets include both viral and host proteins. The experimental designs are supported by strong preliminary data including activity in established mouse models of infection.

Extensive interactions with other Projects will be implemented to ensure that small molecule inhibitors will be developed from targeting through pre-IND studies. There is also a great potential that inhibitors from this project will have synergetic effects with inhibitors developed by other projects in the program to constitute effective combination therapies.