h-89 and Respiratory-Syncytial-Virus-Infections

Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in young children and high-risk adults. However, a specific treatment for this viral infection is not currently available. In this study, we discovered that an exchange protein directly activated by cyclic AMP (EPAC) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, treatment with EPAC inhibitor (ESI-09), but not protein kinase A inhibitor (H89), significantly inhibits RSV replication and proinflammatory cytokine/chemokine induction. In addition, RSV-activated transcriptional factors belonging to the NF-κB and IRF families are also suppressed by ESI-09. Through isoform-specific gene knockdown, we found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and virus-induced host responses. Experiments using both EPAC2 knockout and EPAC2-specific inhibitor support such roles of EPAC2. Therefore, EPAC2 is a promising therapeutic target to regulate RSV replication and associated inflammation.

Topics: A549 Cells; Animals; Cell Line; Chemokines; Cyclic AMP-Dependent Protein Kinases; Guanine Nucleotide Exchange Factors; Humans; Hydrazones; Isoquinolines; Isoxazoles; Mice; NF-kappa B; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; RNA Interference; RNA, Small Interfering; Sulfonamides; Virus Replication