SBIR-STTR Award

Respiratory syncytial virus (RSV) is a major cause of pediatric respiratory disease, resulting in severe lower respiratory tract infection in infants, immunocompromised patients and the elderly. There are no effective antiviral therapies for this disease although an immunoprophylactic antibody is available which reduces the severity of infection in high-risk infants. The development of new therapies for the treatment of RSV infection is a high priority. The initial steps in RSV infection include binding to the target cell and fusion with the cell's plasma membrane. Like HIV, RSV utilizes a protein structure termed a six-helix bundle to drive this membrane fusion event. Disruption of the six-helix bundle formation blocks fusion and infection. The goal of this Phase I project is to develop a prototype screening assay suitable for identifying small molecule inhibitors of RSV six-helix bundle formation. To accomplish this we will develop reagents for the selective detection of the RSV six-helix bundle and characterize the formation of this structure during the initial stages of fusion. This information will be used to develop a prototypic screening assay that will be suitable for use in a high-throughput screening format to detect RSV fusion inhibitors.

Respiratory Syncytial Virus (RSV) is a major disease-causing agent, resulting in severe lower respiratory tract infection in infants, immunocompromised patients, and the elderly. In the U.S. alone it is estimated that RSV is responsible for 125,000 pediatric hospitalizations annually with a mortality rate of greater than 2%. Drugs to treat RSV infection are limited to the broad-spectrum antiviral ribavirin (with unproven efficacy) and the anti-RSV monoclonal antibody Synagis, used for the prophylactic treatment of high-risk infants. These limited options make the development of new therapies for the treatment of RSV infection a high priority. Panacos Pharmaceuticals is involved in the discovery and development of small molecule therapeutics for the treatment of medically important viral diseases including RSV infection. Our proprietary drug discovery program focuses on inhibitors of virus fusion that act by blocking the formation of a key viral entry structure, the six-helix bundle. The goal of the Phase I SBIR project was to develop an approach to identify small molecule RSV fusion inhibitors by adapting the technology that Panacos has used successfully in the past to identify inhibitors of the HIV six-helix bundle. During the Phase I period we generated the necessary reagents to detect the RSV F protein six helix bundle and used these reagents to identify a suitable method for selectively triggering the formation of this structure. We then used this technique to successfully develop a novel high-throughput drug-screen for the identification of small molecule RSV fusion inhibitors. The goal of this Phase H SBIR application is to apply the drug-screening technology developed during the Phase I period to the identification of small molecule RSV fusion inhibitors with properties suitable for clinical development.

Thesaurus Terms:
antiviral agent, drug discovery /isolation, high throughput technology, membrane fusion, respiratory syncytial virus, small molecule, technology /technique development, virus infection mechanism conformation, pharmacokinetics, synthetic protein enzyme linked immunosorbent assay, immunoprecipitation, laboratory rat, nanotechnology, western blotting