Anti-Giradia Cyst Wall Synthase Drugs: In Vivo Testing

Giardia lamblia is a NIAID Biodefense Category B pathogen, causing widespread intestinal infections worldwide. It is the most common waterborne cause of diarrhea in the US. The environmentally resistant, infectious form is the cyst which is transformed into the motile trophozoite form in the small intestine. Some infected people never have disease symptoms but continue to occasionally shed cysts, providing a reservoir for the disease. <P> There are a number of effective drugs to treat giardiasis, however, all either have side effects, are slightly mutagenic, or have problems with resistance. A drug that interrupts cyst excretion and has no mammalian toxicity would greatly improve giardiasis treatment outcomes. <P> We have identified novel inhibitors that affect both trophozoite growth and encystation in vitro. The next step for their development is to test for activity in animal models of disease. <P> In this proposal, we intend to test a lead compound, SP1020 in two models of disease, the suckling mouse model first to determine the optimum treatment dose. Then, the gold standard model, the Mongolian gerbil will be used. A preliminary analysis of drug uptake will also be performed. <P> At the end of the one year application period, we will know whether the candidate compound should be advanced into further pre-clinical studies. <P> PUBLIC HEALTH RELEVANCE By the end of the one year period of this proposal, a proof of concept for the novel class of inhibitors will be accomplished. We intend to have tested one lead compound for efficacy in two in vivo models of Giardiasis, performed an initial pharmacokinetic/toxicology assessment, and determined whether the lead compound should be advanced into phase I clinical trials.