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

Ernest J. Mui, Guy A. Schiehser, Wilbur K. Milhous, Honghue Hsu, Craig W. Roberts, Michael Kirisits, Stephen Muench, David Rice, J. P. Dubey, Joseph W. Fowble, Pradipsinh K. Rathod, Sherry Queener, Susan R. Liu, David P. Jacobus, Rima McLeod

Research output: Chapter in Book/Report/Conference proceedingChapter

36 Scopus citations

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-trifluoromethoxyphenyloxyopropyl 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. gondil and T. gondil 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.

Original languageEnglish
Title of host publicationPLoS Neglected Tropical Diseases
Volume2
Edition3
DOIs
StatePublished - Mar 2008

ASJC Scopus subject areas

  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo'. Together they form a unique fingerprint.

  • Cite this

    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., Liu, S. R., Jacobus, D. P., & McLeod, R. (2008). Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. In PLoS Neglected Tropical Diseases (3 ed., Vol. 2). [e190] https://doi.org/10.1371/journal.pntd.0000190