KSEF RDE: Identification of Anti-Prion Drugs Active against Plant Viruses

Viruses causing devastating diseases in humans, animals and plants are continuous threat to our society. Plant RNA viruses cause tens of millions of dollar loss in Kentucky alone every year. Viruses are difficult to control due to their intracellular replication and continuously evolving nature. Currently, there is no antiviral treatment available after infection of a given plant, which seriously limits the effectiveness of plant virus control. Moreover, viruses frequently develop resistance-breaking strains due to high frequency recombination and mutations. Therefore, there is an urgent need for development of new antivirals to control plant viruses. Viruses need to interact with their host cells to recruit host proteins and subcellular membranes for their replication. These interactions are likely excellent targets for antivirals. Recently, the PI has made significant progress by developing yeast as a model system to study Tomato bushy stunt virus (TBSV) - host interactions. Genome-wide genomics and proteomics screens covering ~95% of all yeast genes led to the identification of over 100 host proteins affecting TBSV replication. Interestingly, a major group of the identified host factors is also known to affect propagation of prions, which are infectious proteins of mammals. Altogether, identification of common host factors in TBSV replication and prion propagation suggests that these infectious agents co-opt overlapping host machinery for their propagation. Indeed, preliminary experiments showed that an antiprion molecule (kastellpaolotine) reduced TBSV replication by 95% in a cell-free TBSV replication assay and in yeast cells. The PI plans to test the inhibitory effect of additional anti-prion kastellpaolotine and phenanthridine molecules in TBSV replication in vitro and in plants. Effort will also be made to identify the inhibitory step in TBSV infection cycle. If successful, the proposed work could lead to patentable new anti plant virus drugs, which could also be tested against animal and human viruses.