A Cell Based HTS Approach for the Discovery of New Inhibitors of RSV

Respiratory Syncitial Virus (RSV) is a highly contagious member of the family Paramyxoviridae. It has been estimated that most children will be infected with RSV prior to their second birthday generating an estimated 75,000 – 125,000 hospitalizations in children. RSV is associated with substantial morbidity and mortality and is the most common cause of bronchiolitis and pneumonia among infants and children under one year of age. Nevertheless, severe lower respiratory tract disease may occur at any age, especially among the elderly or among those with compromised cardiac, pulmonary, or immune systems. There are no vaccines commercially available. Existing therapies for the acute infection are ribavirin and the prophylactic humanized monoclonal antibody (Synagis from MedImmune) that is limited to use in high risk pediatric patients. The economic impact of RSV infections due to hospitalizations and indirect medical costs is greater than $650 million annually; thus, finding inhibitors for RSV would be extensively valuable. The cell-based RSV inhibition screen produced novel compounds that may be developed further into potential prophylactic therapies. Of the 313,816 Molecular Libraries Small Molecule Repository (MLSMR) compounds screened, 51 compounds were selected, based on potency, selectivity and chemical tractability, for further evaluation in dose response and secondary assays. Collaboration between the assay provider, the screening center at Southern Research Institute and the University of Kansas Specialized Chemistry Center narrowed the SAR focus to three scaffolds. The probe, ML232, had an antiviral EC value of 2.25 μM and a 13.7-fold Selectivity Index (SI) for antiviral activity over mammalian cell cytotoxicity.