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

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.

• Authors: 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 F Queener, Susan R Liu, David P Jacobus, Rima McLeod
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 2 Issue 3 Pg. e190 (Mar 05 2008) ISSN: 1935-2735 [Electronic] United States
• PMID: 18320016 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-(2-chloro-4-trifluoromethoxyphenoxy)propyloxy)-1,3,5-triazine
• Antiprotozoal Agents
• Protozoan Proteins
• Triazines
• Tetrahydrofolate Dehydrogenase

Topics

• Amino Acid Sequence
• Animals
• Antiprotozoal Agents (pharmacology, therapeutic use)
• CHO Cells
• Cell Line
• Cricetinae
• Cricetulus
• Enzyme Activation (drug effects)
• Female
• Humans
• Mice
• Molecular Sequence Data
• Protein Structure, Secondary
• Protozoan Proteins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sequence Homology, Amino Acid
• Tetrahydrofolate Dehydrogenase (chemistry, metabolism)
• Toxoplasma (drug effects)
• Toxoplasmosis (drug therapy, parasitology)
• Triazines (pharmacology, therapeutic use)