KSEF RDE: Allosteric Inhibitors of Cellular Hsp70 to Inhibit Virus Replication

Rationale: Viruses are widespread pathogens causing many devastating diseases in plants, animals and humans. The PI lab has identified several hundreds of cellular factors that affect viral replication. A key discovery from the PI's work is the essential role of the co-opted cellular heat shock protein 70 in plant and insect virus replication. Method: The PI will identify and characterize the most potent allosteric inhibitors of Hsp70s to block plant and insect virus replication. Preliminary work with two allosteric inhibitors of Hsp70 showed complete block of viral replication in plant protoplasts, thus justifying the potential of this novel approach. Significance: This work has the potential to obtain a novel effective antiviral approach that has several advantages over traditional viral targets. The advantages include broader antiviral effects against many related and possibly even unrelated viruses and more durable antiviral effects since viruses will have more difficult challenge to evolve mutants that can use other alternative host factors in place of the targeted Hsp70 host factor. Based on the possible broad antiviral effect of these allosteric inhibitors of Hsp70, which are highly conserved from plants to animals, Kentucky would greatly benefit from developing this novel antiviral approach. Impact statement: This proposal likely leads to the identification of novel antiviral compounds. Based on the previous discoveries by the PI on virus-host interactions and the factors involved, the PI will test small molecule allosteric inhibitors of heat shock protein 70, which could potentially block the replication of several plant and insect viruses. Thus, this research could lead to new antiviral drugs with broad antiviral activities. This innovation is expected to help Kentucky agriculture, whose growth is threatened by viruses. The proposed research is also expected to promote medical research in the long-term, too, because the antiviral compounds could have inhibitory effect on human viruses. In addition, viruses are emerging and dangerous pathogens in agriculture and medicine, thus the training of virologist in the PI lab will contribute to increased knowledge in Kentucky.