Small Molecule Antiviral Agents Against Flaviviruses

Flaviviruses, and dengue viruses in particular, are significant human pathogens. No vaccine or specific therapeutic agent is available against West Nile and dengue viruses. Our goal is to develop peptide-derived therapeutics active against West Nile virus, dengue viruses, and other flaviviruses. In Phase I of this project, we identified several candidate tetrapeptides able to neutralize multiple flaviviruses in in-vitro assays. These very short peptides have a molecular weight below 500, affording them the favorable drug characteristics of small molecules. In Phase II, we will further investigate and optimize these hit peptides against flaviviruses. We will systematically vary the composition of our initial hits to obtain variants with greater efficacy. We will also confirm the mechanism of action of the antiviral peptides by verifying that they block the entry of viruses into host cells. Successful completion of these Phase II experiments will place us in an excellent position to initiate testing in animal models of flavivirus diseases during Phase III of this project.