Submitted to: PLOS Neglected Tropical Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2007
Publication Date: 3/1/2008
Citation: Mui, E.J., Schiehser, G.A., Milhous, W.K., Hsu, H., Roberts, C.W., Kirisits, M., Muench, S., Rice, D., Dubey, J.P., Fowble, J.W., Rathod, P.K., Queener, S.F., Liu, S.R., Jacobus, D.P., Mcleod, R. 2008. Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. PLOS Neglected Tropical Diseases. 2(3):e190. Interpretive Summary: Toxoplasma gondii is a single-celled parasite of all warm-blooded hosts worldwide. It causes mental retardation and loss of vision in children, and abortion in livestock. Cats are the main reservoir of T. gondii because they are the only hosts that can excrete the resistant stage (oocyst) of the parasite in the feces. Humans become infected by eating undercooked meat from infected animals and food and water contaminated with oocysts. Toxoplasmosis causes mortality in many species of animals in the zoos, especially wallabies. Scientists at the Beltsville Agricultural Research Center and University of Chicago Medical School report on the finding of a new drug to treat toxoplasmosis. The results will be of interest to biologists, parasitologists, public health workers, and veterinarians
Technical Abstract: JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 (1-(3-(2-chloro-4-trifluoromethoxyphenyloxypropyl) oxy- (5-isopropyl) biguanide, which is being advanced to clinical trials for malaria. Efficacy of the prodrug JPC-2056 and the active metabolite JPC-2067-B against T. gondii and T. gondii DHFR as well as toxicity toward mammalian cells were tested. Herein, we found that JPC-2067-B is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM), inhibits the purified enzyme (IC50 6.5 nM), is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the U.S., Canada, China and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. JPC-2067-B and JPC-2056 have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.