Leishmania major nucleoside hydrolase inhibitors

利什曼原虫主要核苷水解酶抑制剂

基本信息

批准号：
7269652
负责人：
Claude P Selitrennikoff
金额：
$ 10.2万
依托单位：
MYCOLOGICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-04 至 2008-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7269652
关键词：
AIDS/HIV problem Adult Affect Anti-Bacterial Agents Antibiotics Antifungal Agents Antimony Antiviral Agents Clinical Treatment Clinical Trials Collaborations Colorado Communicable Diseases Country Cutaneous Leishmaniasis Developed Countries Developing Countries Disease Drug usage Economic Development Effectiveness Emerging Communicable Diseases Enzymes Exposure to Frequencies Goals Growth HIV Human In Vitro Incidence India Infection Lead Leishmania Leishmania major Leishmaniasis Miltefosine Modeling North America Nucleoside Hydrolases Numbers Patients Pharmaceutical Preparations Phase Phlebotominae Poison Prevention Reporting Research Resistance Resistance development Risk Rural Sand Flies Services Small Business Technology Transfer Research Source Structure Testing Tropical Disease United States Universities Upper arm Uracil Uridine Visceral Leishmaniasis Woman Work Yeasts Zoonoses base cytotoxicity drug development environmental change enzyme activity experience in vivo inhibitor/antagonist macrophage men novel nucleoside inhibitor urban area vaccine development vector

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 has assumed importance in the United States as many of our armed services men and women are being exposed to sand flies and are afflicted with leishmaniasis. Ominously, visceral leishmaniasis has been reported in North America. Leishmania/HIV co-infection is emerging as an extremely serious, new disease and it is increasing in frequency. Leishmania-HIV co-infection is regarded as an "emerging" infectious disease for, in certain countries, up to 70% of adult cases of leishmaniasis are related to HIV/AIDS. Treatment is based primarily on pentavalent antimony compounds. Unfortunately, the antimony compounds are toxic and resistance in various endemic regions is common. Unfortunately, experience with antibiotics, including antibacterials, antifungals, and antivirals, indicates that resistance to currently-used drugs is the rule rather than the exception; this necessitates the continued search for new drugs. Our long-term corporate goal is the identification and development of drugs for the treatment of a number of human infectious diseases, including Leishmania. We will exploit the availability of ~140,000 compounds whose structures and mammalian cytotoxicity are known and the availability of a unique strain of yeast whose growth in dependent on the activity of the essential Leishmania nucleoside hydrolase enzyme. In this Phase I STTR work, we will continue with our successful collaboration with Dr. Richard Titus of Colorado State University and we will screen 15,000 compounds for activity against the nucleoside hydrolase using a novel in vitro screen. Compounds identified in this screen will then be tested for their effect on the growth of L. major in vitro and in a macrophage model of infection. Resulting compounds will then be tested for their effects on in vitro nucleoside hydrolase enzyme activity. We anticipate that in this work we will identify compounds that are active against L. major and have a specific mode of action, that is, are nucleoside hydrolase inhibitors. Leishmaniasis is a serious disease afflicting not only the poor of the New and Old Worlds, but also patients with HIV. Current treatments are toxic and often ineffective showing that new drugs are needed. We expect that our work will lead to new compounds with a specific and known mechanism of action that will be useful for the treatment of human 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。由于我们的许多武装部队男女都暴露于沙蝇，并患有利什曼病。北美据报道，据报道，内脏利什曼病。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。利什曼原虫-HIV共同感染被认为是一种“新兴”的传染病，在某些国家，多达70％的利什曼病病例与艾滋病毒/艾滋病有关。治疗主要基于五价锑化合物。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。不幸的是，具有抗生素的经验，包括抗菌药物，抗真菌剂和抗病毒药，表明对当前使用的药物的抵抗是规则而不是例外。这需要继续寻找新药。我们的长期公司目标是鉴定和开发药物，用于治疗包括利什曼尼亚在内的许多人类传染病。我们将利用〜140,000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，并且具有独特的酵母菌菌株的可用性，其生长取决于必需的利什曼原虫核苷水解酶的活性。在这一阶段I STTR工作中，我们将继续与科罗拉多州立大学的理查德·泰特斯（Richard Titus）博士进行成功的合作，并将使用新颖的体外筛查筛选15,000种化合物，以针对核苷水解酶进行活动。然后，将测试在此筛选中鉴定出的化合物，以便它们对大乳杆菌体外和感染巨噬细胞模型的影响。然后，将测试所得化合物对体外核苷水解酶活性的影响。我们预计，在这项工作中，我们将确定对L. Major的活性并具有特定作用方式的化合物，即核苷水解酶抑制剂。利什曼病是一种严重的疾病，不仅遭受了新的和旧世界的穷人的困扰，而且遭受了艾滋病毒患者。当前的治疗是有毒的，通常无效地表明需要新药。我们预计我们的工作将带来新的化合物，具有特定的，已知的作用机理，可用于治疗人类利什曼病。