A NOVEL THERAPEUTIC TREATMENT FOR TOXOPLASMOSIS AND MALARIA
- 技术优势
- Selective inhibition of T. gondii OAT and P. falciparum OAT over human OAT Greater selectivity and potency than conventional inhibitors Targeted s sporozoites, the most common source of parasite infection
- 详细技术说明
- Selective inactivation of ornithine aminotransferase for treating toxoplasmosis and malaria #chemical #medicinal #healthcare #therapeutics #drugdiscovery
- *Abstract
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BACKGROUND
Toxoplasmosis, the disease caused by the parasite Toxoplasma gondii (T. gondii), is the leading cause of death attributed to food-borne illness in the United States. Another parasite Plasmodium falciparum (P. falciparum) is responsible for roughly 50% of all malaria cases. One potential therapeutic target in the fight against these parasites is ornithine aminotransferase (OAT), an enzyme that plays a crucial role in preventing toxic accumulation of ornithine in the cell. Selective inhibition of OAT in T. gondii (TgOAT) and P. falciparum (PfOAT) over human OAT is highly desired in either eliminating the growth of the parasites or preventing the shedding of long lived and persisting infectious oocysts into the environment. Current therapeutics for T. gondii and P. falciparum have limitations, including toxicity, hypersensitivity reactions, an inability to eliminate the latent, encysted bradyzoite life stage of T. gondii, and malaria drug resistance. For these reasons, new therapeutic approaches are needed.
ABSTRACT
Northwestern inventors have discovered a compound that selectively inactivates forms of OAT specific for T. gondii and P. falciparum, which causes toxoplasmosis and malaria, respectively. After characterizing a number of features of TgOAT, including the gene, protein, abundance in different life cycle stages, and enzyme activity, they screened a library of 23 GABA analogues and identified several inactivators, specific for TgOAT and PfOAT, but not human OAT. Crystal structures of the native and inactivated enzymes were obtained, shedding light on the structural changes in the enzyme binding pocket. In addition to this selective activity, the compound also uniquely targets all stages of the parasite life cycle, but is most effective in the sporozoite stage, which is the most implicated form for disease transmission. Expression of Tg/PfOAT is ~256 times higher in sporozoites (oocyst) than in tachyzoites and bradyzoites which are the active and dormant forms. Targeting the environmentally-resistant oocyst life cycle stage could have a significant impact on disrupting the chain of transmission and, thereby, decrease the consequent morbidity and mortality. These newly identified Tg/PfOAT inactivators and insights drawn from crystal structures lay a foundation of further studies of selective inactivation of Tg/PfOAT and drug development.
- *Inventors
- Richard Silverman* Hoang Le Rima McLeod
- 国家/地区
- 美国
