New drugs for the treatment of leishmaniasis

描述(申请人提供)：利什曼原虫是一种典型的原生动物，由血吸虫沙蝇传播，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个国家被认为是发展中国家。据估计，有3.5亿人面临被不同种类的利什曼原虫感染的风险。每年新发病例约200万例(皮肤利什曼病150万例，内脏利什曼病50万例)。与许多其他热带疾病一样，利什曼病与经济发展和人为环境变化有关，这增加了对沙蝇媒介的接触。这种疾病在美国变得重要起来，因为许多沙漠风暴退伍军人接触到了沙蝇，并患有利什曼病。利什曼病/艾滋病毒混合感染正在成为一种极其严重的新疾病，而且其频率正在增加。治疗主要是基于五价锑化合物，尽管一种新药米替福辛在治疗利什曼病方面表现出了希望。不幸的是，锑化合物是有毒的，在不同的流行地区，耐药性很常见。米替福辛最近才在印度获得批准，其在现场的有效性和耐药性的发展尚不清楚。我们将利用大约140,000个化合物的可用性，这些化合物的结构和哺乳动物细胞毒性已知，但尚未筛选出抗利什曼原虫活性。在第一阶段的工作中，我们将筛选15,000种化合物的抗利什曼原虫活性，并首先在体外测试化合物的有效性，然后在体内测试化合物的有效性。我们将通过两个具体目标来实现这一点：目标一：筛选15,000个化合物的体外抗利什曼原虫活性。活性化合物将被筛选出来对抗真菌和细菌，只有对哺乳动物细胞没有毒性的利什曼原虫特有的化合物将被用培养的利什曼原虫感染的巨噬细胞进行体外有效性测试。目的二：那些在体外对利什曼原虫有毒性的化合物将在主要利什曼原虫感染的小鼠皮肤模型上进行测试。被发现具有体内活性的化合物将在第二阶段得到进一步开发，另外还有125,000种化合物进行了活性筛选。最终，这项工作将导致确定一种用于治疗利什曼病的人类临床试验的先导化合物。

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.