Poster abstracts
Poster number 28 submitted by Paul Kelly
Identification of Aminoacyl-tRNA Synthetase Inhibitors against Eukaryotic Pathogens
Paul Kelly (Molecular, Cellular, and Developmental Biology Program, Ohio State University), Tammy Bullwinkle (Department of Microbiology, Ohio State University), David Ardell (Program in Quantitative Systems Biology, University of California, Merced), Roger Linington (Department of Chemistry, Simon Fraser University), Abhay Satoskar (Department of Microbiology and Department of Pathology, Ohio State University), Michael Ibba (Department of Microbiology, Ohio State University)
Abstract:
While antibiotics have been developed to specifically target prokaryotic cellular machinery, developing therapies against eukaryotic pathogens has proven to be more challenging due to conservation between potential pathogen drug targets and their host counterparts. Previous studies have identified antifungal therapies that target pathogen aminoacyl-tRNA synthetases (aaRS) with some degree of specificity, indicating that these essential enzymes could be developed as drug targets for a variety of infections. AaRS transfer amino acids on to their corresponding tRNA in a two-step process: 1) binding to the free cognate amino acid in an ATP-dependent manner (activation) and 2) aminoacylation of the amino acid on to the cognate tRNA (transfer). Using bioinformatic and in vitro biochemical analysis, we have identified alanyl-tRNA synthetase (AlaRS) in the eukaryotic parasite, Leishmania major as a potential target for antileishmanial therapies. Furthermore, preliminary identification of potential inhibitors prevented amino acid activation of the L. major AlaRS but had no effect on the human counterpart enzyme. Future studies look to determine the mechanism of action of these inhibitors and determine the broad spectrum potential of these inhibitors against other eukaryotic pathogens.
Keywords: Aminoacyl-tRNA synthetase, tRNA, Drug Discovery