Antiviral Countermeasures Development Center (AC/DC)

The Alphavirus genus includes important human pathogens such as chikungunya virus (CHIKV), Mayaro virus (MAYV), Ross River virus (RRV), and the encephalitic alphaviruses Venezuelan (VEEV), Western (WEEV), and Eastern (EEEV) equine encephalitis viruses. These plus-sense RNA viruses are of significant concern in human health and biodefense, but to date there are no licensed alphavirus vaccines or antiviral therapies. Alphavirus RNA replication is mediated by the concerted and coordinated action of the 4 non-structural proteins (nsP1-4). Recent advances in our structural and functional understanding of the alphavirus nsPs strongly support the replication complex as a target for antiviral therapy. This project aims to develop small molecule inhibitors of alphavirus RNA replication, building on promising preliminary findings of inhibition by nucleosides and by inhibitors of the essential nsP2 protease. We will use cell-based CHIKV replicon systems and a novel cell-based nsP2 protease assay to screen for small molecule inhibitors of alphavirus replication. We will define their mechanisms of action using our battery of cell-free and cell culture systems, and test in vivo efficacy using mouse models of acute and chronic CHIKV infection and disease and a novel reporter mouse system. The project takes advantage of the broad expertise of the investigative team in alphavirus entry, RNA replication, exit, and in vivo infection models, capitalizes on the small molecule inhibitors already identified, and leverages the cores of the U19, together strongly supporting the goal of developing direct acting antiviral therapies against alphaviruses