Abstract
Respiratory syncytial virus (RSV) is responsible for majority of infant hospitalizations due to viral infections. Despite its clinical importance, no vaccine against RSV or effective antiviral therapy is available. Several structural classes of small-molecule RSV entry inhibitor have been described and one compound has advanced to clinical testing. Mutations in either one of two resistance hot spots in the F protein mediate unusual pan-resistance to all of these inhibitor classes. Based on the biochemical characterization of resistant viruses and structural insight into the RSV F trimer, we propose a kinetic escape model as the origin of pan-resistance. Since a resistant RSV remained pathogenic in the mouse model, pan-resistance mutations could emerge rapidly in circulating RSV strains. We evaluate clinical implications and discuss consequences for the design of future RSV drug discovery campaigns.