Nucleoside hydrolase Inhibitors from natural products for Leishmania

来自天然产物的利什曼原虫核苷水解酶抑制剂

基本信息

批准号：
7805752
负责人：
Esteban Edward Mena
金额：
$ 21.17万
依托单位：
LIFEPHARMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7805752
关键词：
Affect Afghanistan Agaricales Ascomycota Basidiomycota Biological Factors Bite Chemicals Chemoprophylaxis Colorado Country Cutaneous Leishmaniasis Developing Countries Development Disease Economics Enzymes Frequencies Goals Growth Gulf War Human In Vitro Infection Iraq Kuwait Laboratories Lead Leishmania Leishmania major Leishmaniasis Libraries Location Mammals Military Personnel Modeling Mus Nucleoside Hydrolases Parasites Pharmaceutical Preparations Phase Procedures Public Health Reporting Risk Sampling Sand Flies Screening procedure Small Business Innovation Research Grant Soldier Source Testing Therapeutic Toxic effect United States Universities Uracil Uridine Veterans Work Yeasts Zoonoses base effective therapy high throughput screening in vitro Model in vitro activity inhibitor/antagonist macrophage meetings novel public health relevance research study scaffold therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Our goal is to identify novel drugs for the treatment and chemoprophylaxis of Leishmania by blocking nucleoside hydrolase (NH) activity of this parasite. 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 disease assumed importance in the United States as many Desert Storm veterans were exposed to sand flies; approximately 700 confirmed cases of cutaneous leishmaniasis were reported in 2003-2004 in soldiers returning from Iraq and Kuwait. Leishmania/HIV co-infection is emerging as an extremely serious, new disease and it is increasing in frequency. The Leishmania nucleoside hydrolase is an excellent candidate as a target for safe and effective pan-Leishmania drugs. These include i) the absence of NH activity in mammals, ii)its intracellular location, iii) and its constitutive expression in promastigotes (the infective form transmitted by phlebotomine sand flies. We combined LifePharms' novel natural product library consisting of 120,000 semipurified compounds from field collected basidiomycetes and ascomycetes with MycoLogics' yeast-based HTS for Leishmania nucleoside hydrolase (NH) inhibitors. From the 15,000 samples already screened, we identified 4 compounds that inhibit NH and are Leishmanicidal active against L. major promastigotes in culture. Here we propose to i) determine if the isolated lead compounds are active against infected mouse and human macrophages in vitro, ii). Isolate additional amounts of lead compound and chemically identify the active compounds, iii) screen an additional 30,000 samples from LifePharms semipure compound library for in vitro activity using a MycoLogics' proprietary strain of yeast that requires the activity of the Leishmania major nucleoside hydrolase for growth on uridine as the sole source of uracil and the in vitro models of leishmaniasis. PUBLIC HEALTH RELEVANCE: Leishmaniasis is a major public health risk throughout much of the tropical and subtropical world. The disease has assumed importance in the United States for due to presence of the US military in the Gulf War and it current deployments to Iraq and Afghanistan many soldiers are bitten by sand flies and develop classic leishmaniasis presentations. Also, there is a concern that leishmaniasis could become more widespread in the United States. Our goal is to identify compounds that can be developed for the effective treatment of Leishmaniasis.

描述（由申请人提供）：我们的目标是通过阻断该寄生虫的核苷水解酶（NH）活性来鉴定利什曼原虫的治疗和化学预防药物的新药物。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。由于许多沙漠风暴退伍军人暴露于沙蝇，这种疾病在美国具有重要意义。 2003年至2004年，大约有700例确认的皮肤利什曼病病例是从伊拉克和科威特返回的士兵。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。 Leishmania核苷水解酶是成为安全有效的泛利什曼菌药物的靶标。其中包括i）哺乳动物中缺乏NH活性，ii）其细胞内位置，iii）及其在前寄生植物中的组成型表达（通过静脉芽孢杆菌蝇传播的感染形式。我们合并了Lifepharms的新型自然产品库，该新型自然产品图书馆与现场收集的基本基底式化合物一起，与ASCOMYCOTES的基本基本型组合，ASCOMYCETES，ASCOMYCETS'Mycycets Mycycets'Mycycets'Mycycets'Mycycets'利什曼原虫核苷水解酶（NH）抑制剂已经筛选了15,000个样品，我们确定了4种抑制NH的化合物，并且在这里抑制了Leishmanicidal Active of LeishManicidal Active，我们在这里提出的是I）。分离株额外的铅化合物和化学识别活性化合物，iii）筛选来自Lifepharms半膜化合物库中的另外30,000个样品，使用真菌学专有酵母的体外活性，该酵母需要Leishmania主要的核苷水解酶的活性，以使尿酸含量的尿素源和VERISH模型的尿素源为尿素，以实现尿中的含量。公共卫生相关性：利什曼病是整个热带和亚热带世界的主要公共卫生风险。由于美国军方在海湾战争中的存在，该疾病在美国很重要，并且目前向伊拉克和阿富汗部署了许多士兵，许多士兵被沙蝇咬伤，并发展了经典的利什曼病。同样，人们担心利什曼病在美国可能变得更加普遍。我们的目标是确定可以开发出可为利什曼病的有效治疗而开发的化合物。