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New drugs for the treatment of leishmaniasis

治疗利什曼病的新药

基本信息

批准号：
6832750
负责人：
Claude P Selitrennikoff
金额：
$ 10万
依托单位：
MYCOLOGICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-20 至 2004-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6832750
关键词：
India Leishmania major antiprotozoal agents cytotoxicity drug discovery /isolation drug screening /evaluation host organism interaction laboratory mouse leishmaniasis macrophage tissue /cell culture

项目摘要

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 assumed importance in the United States as many Desert Storm veterans were exposed to sand flies and were afflicted with Leishmaniasis. Leishmania/HIV co-infection is emerging as an extremely serious, new disease and it is increasing in frequency. Treatment is based primarily on pentavalent antimony compounds although a new drug, miltefosine, shows promise in treating leishmaniasis. Unfortunately, the antimony compounds are toxic and resistance in various endemic regions is common. Miltefosine has only been recently approved in India and its effectiveness in the field and the development of resistance are unknown. We will exploit the availability of approximately 140,000 compounds whose structures and mammalian cytotoxicity are known and which have not been screened for anti-Leishmania activity. In the Phase I work, we will screen 15,000 compounds for anti-Leishmania activity and test compounds for efficacy first in vitro and then in vivo. We will accomplish this in Two Specific Aims: Aim One: Screen 15,000 compounds for in vitro activity against Leishmania. Active compounds will be screened against fungi and bacteria and only Leishmania specific compounds that have no mammalian cell toxicity will be tested for in vitro efficacy with cultures Leishmania-infected macrophages. Aim Two: Those compounds that are toxic for Leishmania in vitro will then be tested in a cutaneous murine model of L. major infection. Compounds that are found to have in vivo activity will be developed further in Phase II as well as an additional 125,000 compounds screened for activity. Ultimately, this work will lead to the identification of a lead compound for human clinical trials for the treatment of leishmaniasis.

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。这种疾病在美国很重要，因为许多沙漠风暴退伍军人接触过沙蝇，患上了利什曼病。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。治疗主要基于五价锑化合物，尽管一种新药米特福辛在治疗利什曼病方面显示出希望。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。米特福辛最近才在印度获得批准，其在实地的有效性和耐药性的发展尚不清楚。我们将利用大约14万种化合物的可用性，这些化合物的结构和哺乳动物细胞毒性是已知的，并且尚未进行抗利什曼原虫活性筛选。在第一阶段的工作中，我们将筛选15000种抗利什曼原虫活性的化合物，并首先在体外和体内测试化合物的功效。我们将在两个具体目标中实现这一目标：目标一：筛选15000种化合物体外抗利什曼原虫活性。活性化合物将对真菌和细菌进行筛选，只有对哺乳动物细胞没有毒性的利什曼原虫特异性化合物将在培养的感染利什曼原虫的巨噬细胞中进行体外功效测试。目标二：这些化合物在体外对利什曼原虫有毒性，然后将在大利什曼原虫感染的皮肤小鼠模型中进行测试。被发现具有体内活性的化合物将在II期进一步开发，另外还有125,000种化合物进行活性筛选。最终，这项工作将导致鉴定出用于治疗利什曼病的人体临床试验的先导化合物。