Broad Spectrum Anti-viral Compounds Targeting the SKI Complex

The RNA Exosome and SKI complex are major cellular machines that degrade host RNA. Thismachine is required for several reasons in the cell including maintenance of current RNA levelsand to reduce the level of cytoplasmic RNA such that the RIGI and MDA5 sensors can detect viralRNA other than host RNA. The SKI complex was identified in a genetic screen as a host proteinthat interacts with both Influenza NS1 and MERS-CoV ORF4a. We were able to demonstrate thatknocking down these proteins in cells caused a reduction in viral replication and an increase inInterferon stimulated gene induction, irrespective of whether a virus was there or not. The SKIcomplex in yeast has been crystalized and upon modeling of the human structure, we in silicoidentified compounds that could potentially bind to a member of the complex, WDR61. In cellculture experiments, we identified 4 compounds from the 40 identified in the modeling, that blockInfluenza virus, MERS-CoV and SARS-CoV replication. In this proposal, we will determine themechanism of action of the compounds and NS1 and ORF4a on the SKI complex. We will alsoinitiate in vivo studies to evaluate the antiviral effectiveness of the SKI targeted plasmids onInfluenza virus and MERS-CoV mouse models. This work will validate a novel host target andcompounds directed at the SKI complex as broadly acting antivirals.