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

• 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
• 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

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利什曼原虫的核苷水解酶（NH）活性来鉴定治疗和化学预防利什曼原虫的新药。利什曼病是一种人畜共患病，影响88个国家的1 200万人，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。这种疾病在美国变得很重要，因为许多沙漠风暴退伍军人暴露于白蛉; 2003-2004年在从伊拉克和科威特返回的士兵中报告了大约700例皮肤利什曼病确诊病例。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，并且频率正在增加。利什曼原虫核苷水解酶是一个很好的候选人作为一个安全和有效的泛利什曼原虫药物的目标。这些包括i）哺乳动物中NH活性的缺乏，ii）其细胞内位置，iii）及其在前鞭毛体（由白蛉白蛉传播的感染形式）中的组成型表达。 我们将LifePharms的新型天然产物库与MycoLogics的基于酵母的HTS相结合，该天然产物库由来自野外收集的担子菌和子囊菌的120，000种半纯化化合物组成，用于利什曼原虫核苷水解酶（NH）抑制剂。从已经筛选的15，000个样品中，我们鉴定了4种抑制NH的化合物，并且对L.主要的前鞭毛体。在此，我们提出i）确定分离的先导化合物是否在体外对感染的小鼠和人巨噬细胞具有活性，ii）。分离额外量的先导化合物并化学鉴定活性化合物，iii）使用MycoLogics的专有酵母菌株和利什曼病的体外模型，从LifePharms半纯化合物文库中筛选额外的30，000个样品的体外活性，所述酵母菌株需要主要利什曼原虫核苷水解酶的活性以在尿苷上生长作为尿嘧啶的唯一来源。 公共卫生相关性：利什曼病是热带和亚热带世界大部分地区的主要公共卫生风险。这种疾病在美国已经占据了重要地位，因为由于美国军队在海湾战争中的存在，以及目前部署到伊拉克和阿富汗的许多士兵被沙蝇咬伤，并发展成经典的利什曼病。此外，人们担心利什曼病可能在美国变得更加普遍。我们的目标是确定可以开发用于有效治疗利什曼病的化合物。