PI: VERMEIRE, JON J. Project: 1K22AI089969-01 Title: Defining target specificity of oxadiazole 2-oxides in Ancylostoma ceylanicum Accession Number: 3233568 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== J. Vermeire - Project Summary/Abstract Hookworms remain a major health burden in the developing world, with hundreds of millions currently afflicted by these bloodfeeding parasites. Future efforts to substantially reduce hookworm disease will likely require the joining of conventional control methods with alternative strategies such as vaccines and novel therapeutics. Development of such strategies requires identification of targets essential for parasite survival. In this regard hookworm enzymes involved in bloodmeal metabolism are attractive drug and vaccine targets. In addition to providing essential nutrients, bloodfeeding also exposes hookworms to potentially toxic iron-containing compounds, which mediate the generation of free radicals and oxidative products. Thus, it is highly likely that the adult hookworm, which feeds aggressively on host blood, has evolved an efficient mechanism for detoxifying the reactive oxygen species that are generated through hemolysis of red blood cells and protease mediated digestion of hemoglobin. Antioxidant systems of bloodfeeding, intestinal nematodes represent an extremely important yet understudied area of helminth biology. Therefore, one important aspect of the proposal includes characterization of hookworm antioxidant pathways in order to better understand their role in parasite biology and host pathogenesis. The other focus of the research outlined in the proposal is to define the target(s) of oxadiazole 2-oxides in the human hookworm Ancylostoma ceylanicum. Preliminary data reveal that these nitric oxide-donating compounds are highly toxic to the adult stages of A. ceylanicum. Recent work has identified oxadiazoles as lead compounds targeting the trematode multifunctional redox protein, thioredoxin glutathione reductase (TGR), and suggest their efficacy as new drugs for helminths. Hookworms do not express this gene product, instead relying on separate enzymes for thioredoxin and glutathione reductase activities. Therefore, the mechanism by which oxadiazoles kill hookworms remains unknown. The proposed experiments are designed to 1) systematically identify and characterize the thiol redox pathways in A. ceylanicum, 2) define target specificity and inhibitory action of oxadiazole compounds on A. ceylanicum redox pathway members, and 3) abrogate adult A. ceylanicum redox activities in vivo using neutralizing antibodies and oxadiazole compounds. The experimental design includes methodologies that will allow the PI to develop technical skill in areas critical to future success. The proposal specifically outlines how K22 support will augment and build upon the PI's previous research experience and postdoctoral training by providing essential opportunities for scientific development and professional growth. Funding of this K22 award will maximize the potential of the PI to establish himself as an independent investigator in order to make a meaningful contribution to the field of molecular helminthology. J. Vermeire -
The experiments delineated in this proposal are designed to characterize hookworm antioxidant pathways and the effect of a new class of lead drug compounds on their activity. This is directly relevant to public health because it will provide information about the role of these enzymes in parasite biology and host disease. Information gained from these experiments may directly contribute to the development of new drugs for the treatment of human hookworm disease.