Characterization of an orally available respiratory syncytial virus L protein polymerase inhibitor DZ7487.

objectivesRespiratory Syncytial Virus (RSV) is a leading cause of death and hospitalization among infants and young children. People with an immunocompromised status are also at risk for severe RSV infection. There is no specific treatment for RSV infection available. Ribavirin, an antiviral drug approved for severe lung infection by RSV, has shown limited clinical efficacies with severe side effects. Additionally, given the genetic variability of RSV genomes and seasonal change of different strains, a broad-spectrum antiviral drug is highly desirable. The RNA-dependent RNA polymerase (RdRp) domain is relatively conserved and indispensable for the replication of the virus genome and therefore serves as a potential therapeutic target. Previous attempts to identify an RdRp inhibitor have not been successful due to lack of potency or high enough blood exposure. DZ7487 is a novel orally available small molecule inhibitor specifically designed to target the RSV RdRp. Here we present our data showing that DZ7487 can potently inhibited all clinical viral isolates tested, with large safety margin predicted for human.

methodsHEp-2 cells were infected by RSV A and B. Antiviral activities were assessed by

resultsDZ7487 potently inhibited viral replication of all clinical isolates of both RSVA and B subtypes. In lower airway cells, DZ7487 showed superior efficacy than the nucleoside analog ALS-8112. Acquired resistant mutation was predominantly restricted at the RdRp domain resulting asparagine to threonine mutation (N363T) of the L protein. This finding is consistent with DZ7487's presumed binding mode. DZ7487 was well tolerated in animal models. Unlike fusion inhibitors, which can only prevent viral infection, DZ7487 potently inhibited RSV replication before and after RSV

conclusionsDZ7487 demonstrated potent anti-RSV replication effect both in vitro and in vivo assays. It has the desired drug-like physical properties to be an effective orally available anti-RSV replication drug with broad spectrum.