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）：利什曼原虫是通过静脉菌菌sand蝇传播的typanosomatid原生动物，导致利什曼病。利什曼病是人畜共患病，在88个国家中影响1200万人，其中72个被认为是发展中国家。据估计，有3.5亿人有利什曼尼亚种类的感染风险。新病例的年发病率约为200万（150万皮肤利什曼病和50万内脏利什曼病）。像许多其他热带疾病一样，利什曼尼亚人与经济发展和人造环境变化有关，这增加了对砂蝇载体的接触。由于许多沙漠风暴退伍军人暴露于沙蝇，并遭受了利什曼病的折磨，这种疾病在美国很重要。利什曼原虫/艾滋病毒共同感染正在成为一种非常严重的新疾病，频率正在增加。治疗主要基于五价锑化合物，尽管一种新药Miltefosine显示出对治疗利什曼病的有希望。不幸的是，锑化合物具有毒性，并且在各个地方性地区的耐药性很常见。米尔特法辛（Miltefosine）最近才在印度获得批准，其在该领域的有效性且抵抗的发展尚不清楚。我们将利用大约14万种化合物的可用性，其结构和哺乳动物的细胞毒性是已知的，并且尚未筛选抗Leishmania活性。在第一阶段的工作中，我们将筛选15,000种抗leishmania活性的化合物和测试化合物，首先是体外，然后在体内进行疗效。我们将在两个具体的目标中实现这一目标：目标：屏幕15,000种针对利什曼尼亚的体外活动。活性化合物将针对真菌和细菌进行筛选，并且只有Leishmania特定的没有哺乳动物细胞毒性的特异性化合物才能测试使用Leishmania感染的巨噬细胞培养物的体外疗效。目标二：那些在体外有毒的化合物将在皮肤乳杆菌的皮肤鼠模型中进行测试。发现具有体内活性的化合物将在II期中进一步开发，以及筛选活动的125,000种化合物。最终，这项工作将导致鉴定人类临床试验的铅化合物治疗利什曼病。