Small Molecule Antiviral Agents Against Flaviviruses

Flaviviruses enter mammalian cells by a mechanism involving a structural rearrangement of the stem region of their envelope protein. The stem region establishes specific molecular contacts with amino acid residues of domain II of the rest of the envelope protein. Our hypothesis is that tetrapeptides that bind to the stem region of flaviviruses will block viral entry and could be used as human therapeutic agents. We will model the configuration of the stem region of West Nile virus (WNV) making contact with domain II, using a process that we used successfully with dengue virus (DV) serotype 1. We will then use advanced proprietary computational methods to design tetrapeptides predicted to bind the stem region in that configuration. The peptides predicted to bind the stem region with the highest affinity will be synthesized and tested in WNV and DV1-4 neutralizing assays. Because the stem region is conserved among flaviviruses, we expect that these peptides will be active against several flaviviruses of medical importance. Our preliminary results support the validity of our approach. We designed tetrapeptides predicted to bind the stem region of DV 1. We found that a portion of these peptides neutralized DV1, and also DV2 and WNV.