Leishmania major nucleoside hydrolase inhibitors

描述（由申请人提供）：利什曼原虫是由白蛉沙蝇传播的typanosomatid原生动物，引起利什曼病。利什曼病是一种人畜共患病，影响88个国家的1200万人，其中72个被认为是发展中国家。据估计，有3.5亿人面临感染不同种类利什曼原虫的风险。每年新发病例约为200万例（皮肤利什曼病150万例，内脏利什曼病50万例）。与许多其他热带病一样，利什曼病与经济发展和人为的环境变化有关，这些变化增加了接触白蛉病媒的机会。这种疾病在美国已经变得很重要，因为我们的许多军人都接触过沙蝇，并受到利什曼病的折磨。不祥的是，在北美已经有内脏利什曼病的报道。利什曼原虫/艾滋病毒合并感染正在成为一种极其严重的新疾病，而且发生频率正在增加。利什曼-艾滋病毒合并感染被视为一种“新出现的”传染病，因为在某些国家，高达70%的成年利什曼病病例与艾滋病毒/艾滋病有关。治疗主要基于五价锑化合物。不幸的是，锑化合物是有毒的，在各个流行地区耐药是常见的。不幸的是，使用抗生素（包括抗菌药、抗真菌药和抗病毒药物）的经验表明，对目前使用的药物产生耐药性是普遍现象，而不是例外；这就需要继续寻找新药。我们的长期企业目标是识别和开发用于治疗包括利什曼原虫在内的许多人类传染病的药物。我们将利用约140,000种结构和哺乳动物细胞毒性已知的化合物，以及一种独特的酵母菌株，其生长依赖于必需的利什曼核苷水解酶的活性。在这个一期STTR工作中，我们将继续与科罗拉多州立大学的Richard Titus博士成功合作，我们将使用一种新的体外筛选方法筛选15,000种化合物，以检测其对核苷水解酶的活性。在此筛选中鉴定的化合物将在体外和感染巨噬细胞模型中测试其对L. major生长的影响。然后将测试所得化合物对体外核苷水解酶活性的影响。我们预计，在这项工作中，我们将确定对L. major有活性的化合物，并具有特定的作用模式，即核苷水解酶抑制剂。

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.