IDENTIFICATION OF SMALL MOLECULE INHIBITORS OF RSV ENTRY

DESCRIPTION (provided by applicant): 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.