Leishmania major nucleoside hydrolase inhibitors

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DESCRIPTION (provided by applicant): Leishmania are typanosomatid protozoans that are transmitted by phlebotomine sand flies causing leishmaniasis. 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 annual incidence of new cases is about 2 million (1.5 million of cutaneous leishmaniasis, and 500,000 of visceral leishmaniasis). Like many other tropical diseases, the leishmaniases are related to economic development and man-made environmental changes, which increase exposure to the sandfly vector. The disease has assumed importance in the United States as many of our armed services men and women are being exposed to sand flies and are afflicted with leishmaniasis. Ominously, visceral leishmaniasis has been reported in North America. Leishmania/HIV co-infection is emerging as an extremely serious, new disease and it is increasing in frequency. Leishmania-HIV co-infection is regarded as an "emerging" infectious disease for, in certain countries, up to 70% of adult cases of leishmaniasis are related to HIV/AIDS. Treatment is based primarily on pentavalent antimony compounds. Unfortunately, the antimony compounds are toxic and resistance in various endemic regions is common. Unfortunately, experience with antibiotics, including antibacterials, antifungals, and antivirals, indicates that resistance to currently-used drugs is the rule rather than the exception; this necessitates the continued search for new drugs. Our long-term corporate goal is the identification and development of drugs for the treatment of a number of human infectious diseases, including Leishmania. We will exploit the availability of ~140,000 compounds whose structures and mammalian cytotoxicity are known and the availability of a unique strain of yeast whose growth in dependent on the activity of the essential Leishmania nucleoside hydrolase enzyme. In this Phase I STTR work, we will continue with our successful collaboration with Dr. Richard Titus of Colorado State University and we will screen 15,000 compounds for activity against the nucleoside hydrolase using a novel in vitro screen. Compounds identified in this screen will then be tested for their effect on the growth of L. major in vitro and in a macrophage model of infection. Resulting compounds will then be tested for their effects on in vitro nucleoside hydrolase enzyme activity. We anticipate that in this work we will identify compounds that are active against L. major and have a specific mode of action, that is, are nucleoside hydrolase inhibitors. Leishmaniasis is a serious disease afflicting not only the poor of the New and Old Worlds, but also patients with HIV. Current treatments are toxic and often ineffective showing that new drugs are needed. We expect that our work will lead to new compounds with a specific and known mechanism of action that will be useful for the treatment of human leishmaniasis.