Broad Institute Inhibition of T.cruzi replication in culture Inhibitor Probe Project
The main goal is to identify new drugs for the treatment of Chagas disease. New drugs are needed because the only two drugs currently available are only effective against the early stages of disease and have significant toxicity to the patient. No drug is available to treat the chronic stage. This assay approach is intended to select drugs that will be effective against the early stages of more ..
Ana Rodriguez,NYU,New York, NY,Ana.Rodriguez@nyumc.org,212 263 6757 (Office)
The main goal is to identify new drugs for the treatment of Chagas disease. New drugs are needed because the only two drugs currently available are only effective against the early stages of disease and have significant toxicity to the patient. No drug is available to treat the chronic stage. This assay approach is intended to select drugs that will be effective against the early stages of disease when parasites are found mainly extracellularly, but also drugs that will be effective against the chronic stage, where parasites are found inside host cells. Therefore we will select drugs that are either trypanostatic (expected to be effective in the acute phase of disease) or trypanocidal (expected to be effective against the chronic stage).
a.Inhibits intracellular parasitic replication (IC50 less than 500 nanomolar)
b.Non-toxic to host cells
c.100-fold selectivity towards inactivation of T. Cruzi vs. host cell toxicity
d.Preference given to Compounds that are trypanocidal
e.Chemically tractable compound
T. cruzi, Trypanosoma cruzi, Chagas
Chagas disease is endemic to 18 Latin American countries, being the major cause of heart failure in the region. Chagas disease is caused by the parasite Trypanosoma cruzi, transmitted to humans in 3 ways: 1) Blood-feeding by various insect vectors that belong to the Reduviidae family, which live in cracks and crevices of poor-quality rural houses or in the wild. They emerge at night to bite and suck blood. The feces of the insects contain parasites, which can enter the wound left after the blood-meal, usually when it is scratched or rubbed; 2) Through transfusion with infected blood, 3) Congenitally, from infected mother to fetus.
The acute effects appear soon after infection and are generally seen in children. Symptoms can include fever, swelling at the site of the insect bite and of the lymph glands, and enlargement of the liver and spleen. The long-term effects can occur up to 20 years after infection. During the chronic phase of the disease, a proportion of patients develop clinical symptoms, which can include irreversible damage to internal organs such as the heart, esophagus and colon. Patients with these late-stage effects become progressively more ill and then die, usually from heart failure.
The number of infected people is estimated to be 13 million. Approximately 25 to 30% of chronically infected patients will suffer from irreversible damage to the heart and digestive tract. This will result in a high incidence of disability and death within the next 20 years, since no drugs are available for treatment of the chronic stage of the parasite. The estimated global burden of the disease is 649,000 disability adjusted life years (the number of healthy years of life lost due to premature death and disability) causing 14,000 deaths per year.
Data Table (Concise)