Alphaviruses are enveloped plus-sense RNA arboviruses that include a number of significant human pathogens that cause arthritis or encephalitis. An important example is chikungunya virus (CHIKV), which causes debilitating acute and chronic arthritis and has emerged as a world-wide public health threat. To date there are no licensed vaccines or antiviral therapies, and Project 6 thus seeks to develop orally available direct-acting antivirals against CHIKV infection. The project relies on the complementary expertise of three investigative teams in New York, Colorado, and Estonia. Our antiviral strategy targets the CHIKV RNA replication complex, which is formed by the coordinated activities of the four alphavirus non-structural proteins (nsP1-4). We will characterize inhibition of CHIKV replication by previously identified nucleoside inhibitors using a range of in vitro assays. We will screen for new inhibitors of CHIKV RNA replication using a cell-based replicon reporter system. We will develop cell-based screens for the essential protease activity of nsP2 and use them to identify novel protease inhibitors. We will use mouse models to characterize promising leads for in vivo efficacy against CHIKV infection and disease. In addition, we will develop a novel reporter mouse line to detect alphavirus-mediated RNA replication, thus enabling us to identify the critical target cells and the effects of antiviral treatment during the acute and chronic phases of CHIKV infection. Together these aims will develop a pipeline of prioritized candidates for antiviral therapeutics.
