Nucleoside hydrolase Inhibitors from natural products for Leishmania

DESCRIPTION (provided by applicant): Our goal is to identify novel drugs for the treatment and chemoprophylaxis of Leishmania by blocking nucleoside hydrolase (NH) activity of this parasite. Leishmaniasis is a zoonosis and affects 12 million people in 88 countries, of which 72 are considered developing countries. It is estimated that 350 million people are at risk to infection by the different species of Leishmania. The disease assumed importance in the United States as many Desert Storm veterans were exposed to sand flies; approximately 700 confirmed cases of cutaneous leishmaniasis were reported in 2003-2004 in soldiers returning from Iraq and Kuwait. Leishmania/HIV co-infection is emerging as an extremely serious, new disease and it is increasing in frequency. The Leishmania nucleoside hydrolase is an excellent candidate as a target for safe and effective pan-Leishmania drugs. These include i) the absence of NH activity in mammals, ii)its intracellular location, iii) and its constitutive expression in promastigotes (the infective form transmitted by phlebotomine sand flies. We combined LifePharms' novel natural product library consisting of 120,000 semipurified compounds from field collected basidiomycetes and ascomycetes with MycoLogics' yeast-based HTS for Leishmania nucleoside hydrolase (NH) inhibitors. From the 15,000 samples already screened, we identified 4 compounds that inhibit NH and are Leishmanicidal active against L. major promastigotes in culture. Here we propose to i) determine if the isolated lead compounds are active against infected mouse and human macrophages in vitro, ii). Isolate additional amounts of lead compound and chemically identify the active compounds, iii) screen an additional 30,000 samples from LifePharms semipure compound library for in vitro activity using a MycoLogics' proprietary strain of yeast that requires the activity of the Leishmania major nucleoside hydrolase for growth on uridine as the sole source of uracil and the in vitro models of leishmaniasis. PUBLIC HEALTH RELEVANCE: Leishmaniasis is a major public health risk throughout much of the tropical and subtropical world. The disease has assumed importance in the United States for due to presence of the US military in the Gulf War and it current deployments to Iraq and Afghanistan many soldiers are bitten by sand flies and develop classic leishmaniasis presentations. Also, there is a concern that leishmaniasis could become more widespread in the United States. Our goal is to identify compounds that can be developed for the effective treatment of Leishmaniasis.