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Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo.

Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble JW, Rathod PK, Queener SF, Liu SR, Jacobus DP, McLeod R - PLoS Negl Trop Dis (2008)

Bottom Line: Herein, we found that JPC-2067-B is highly effective against T. gondii.We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine.JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Science, University of Chicago, Chicago, Illinois, USA.

ABSTRACT

Background and methodology: Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3'(2-chloro-, 4-trifluoromethoxyphenoxy)propyloxy)-1, 3, 5-triazine), which inhibits dihydrofolate reductase (DHFR), is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3'-(2-chloro-4-trifluoromethoxyphenyloxy)propyl oxy)- 5-isopropylbiguanide, 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.

Principal findings and conclusions: 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 (JPC-2056) 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 United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine.

Significance: JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.

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Related in: MedlinePlus

Reduction of numbers of parasites in peritoneal fluid.A. Reduction of numbers by i.p. treatment of mice with JPC-2067-B. B. Reduction of numbers of parasites following treatment of mice with the pro-drug JPC-2056. JPC-2056 was administered by gavage. JPC-2056 is converted into the active compound, JPC-2067-B.
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pntd-0000190-g003: Reduction of numbers of parasites in peritoneal fluid.A. Reduction of numbers by i.p. treatment of mice with JPC-2067-B. B. Reduction of numbers of parasites following treatment of mice with the pro-drug JPC-2056. JPC-2056 was administered by gavage. JPC-2056 is converted into the active compound, JPC-2067-B.

Mentions: JPC-2067-B was also highly effective against T. gondii tachyzoites in a mouse model. A representative experiment with JPC-2067-B is shown in Figure 3A. In the experiment in Figure 3A, mice were infected i.p. with 10,000 tachyzoites of the RH strain of T. gondii for 15 minutes prior to initial treatment with JPC-2067-B.


Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo.

Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble JW, Rathod PK, Queener SF, Liu SR, Jacobus DP, McLeod R - PLoS Negl Trop Dis (2008)

Reduction of numbers of parasites in peritoneal fluid.A. Reduction of numbers by i.p. treatment of mice with JPC-2067-B. B. Reduction of numbers of parasites following treatment of mice with the pro-drug JPC-2056. JPC-2056 was administered by gavage. JPC-2056 is converted into the active compound, JPC-2067-B.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2254147&req=5

pntd-0000190-g003: Reduction of numbers of parasites in peritoneal fluid.A. Reduction of numbers by i.p. treatment of mice with JPC-2067-B. B. Reduction of numbers of parasites following treatment of mice with the pro-drug JPC-2056. JPC-2056 was administered by gavage. JPC-2056 is converted into the active compound, JPC-2067-B.
Mentions: JPC-2067-B was also highly effective against T. gondii tachyzoites in a mouse model. A representative experiment with JPC-2067-B is shown in Figure 3A. In the experiment in Figure 3A, mice were infected i.p. with 10,000 tachyzoites of the RH strain of T. gondii for 15 minutes prior to initial treatment with JPC-2067-B.

Bottom Line: Herein, we found that JPC-2067-B is highly effective against T. gondii.We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine.JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Science, University of Chicago, Chicago, Illinois, USA.

ABSTRACT

Background and methodology: Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3'(2-chloro-, 4-trifluoromethoxyphenoxy)propyloxy)-1, 3, 5-triazine), which inhibits dihydrofolate reductase (DHFR), is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3'-(2-chloro-4-trifluoromethoxyphenyloxy)propyl oxy)- 5-isopropylbiguanide, 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.

Principal findings and conclusions: 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 (JPC-2056) 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 United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine.

Significance: JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.

Show MeSH
Related in: MedlinePlus