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:
- 金额:$ 10.2万
- 依托单位:
- 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:
- 关键词:AIDS/HIV problemAdultAffectAnti-Bacterial AgentsAntibioticsAntifungal AgentsAntimonyAntiviral AgentsClinical TreatmentClinical TrialsCollaborationsColoradoCommunicable DiseasesCountryCutaneous LeishmaniasisDeveloped CountriesDeveloping CountriesDiseaseDrug usageEconomic DevelopmentEffectivenessEmerging Communicable DiseasesEnzymesExposure toFrequenciesGoalsGrowthHIVHumanIn VitroIncidenceIndiaInfectionLeadLeishmaniaLeishmania majorLeishmaniasisMiltefosineModelingNorth AmericaNucleoside HydrolasesNumbersPatientsPharmaceutical PreparationsPhasePhlebotominaePoisonPreventionReportingResearchResistanceResistance developmentRiskRuralSand FliesServicesSmall Business Technology Transfer ResearchSourceStructureTestingTropical DiseaseUnited StatesUniversitiesUpper armUracilUridineVisceral LeishmaniasisWomanWorkYeastsZoonosesbasecytotoxicitydrug developmentenvironmental changeenzyme activityexperiencein vivoinhibitor/antagonistmacrophagemennovelnucleoside inhibitorurban areavaccine developmentvector
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(由申请方提供):利什曼原虫是由白蛉白蛉传播的典型原虫,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3.5亿人面临感染不同种类利什曼原虫的风险。新病例的年发病率约为200万(150万为皮肤利什曼病,50万为内脏利什曼病)。像许多其他热带疾病一样,利什曼病与经济发展和人为的环境变化有关,这些变化增加了对白蛉病媒的接触。这种疾病在美国已经变得很重要,因为我们的许多武装部队的男女都暴露在白蛉中,并受到利什曼病的折磨。不祥的是,内脏利什曼病已在北美报告。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。利什曼病与艾滋病毒合并感染被视为一种“新兴”传染病,因为在某些国家,高达70%的成人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,锑化合物是有毒的,并且在各种流行地区的抗性是常见的。不幸的是,抗生素,包括抗菌药物,抗真菌药和抗病毒药的经验表明,对目前使用的药物的耐药性是规则而不是例外;这需要继续寻找新药。我们的长期企业目标是识别和开发用于治疗包括利什曼原虫在内的多种人类传染病的药物。我们将利用其结构和哺乳动物细胞毒性已知的约140,000种化合物的可用性以及其生长依赖于必需利什曼原虫核苷水解酶活性的独特酵母菌株的可用性。在第一阶段的STTR工作中,我们将继续与科罗拉多州立大学的Richard Titus博士成功合作,我们将使用一种新的体外筛选方法筛选15,000种化合物对核苷水解酶的活性。然后将测试在该筛选中鉴定的化合物对L.主要在体外和巨噬细胞感染模型中。然后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,我们将确定化合物是积极的,对L。主要的和具有特定的作用模式,即是核苷水解酶抑制剂。
利什曼病是一种严重的疾病,不仅困扰着新世界和旧世界的穷人,而且也困扰着艾滋病毒患者。目前的治疗是有毒的,往往无效,表明需要新的药物。我们期望我们的工作将导致具有特定和已知作用机制的新化合物,其将用于治疗人类利什曼病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Claude P Selitrennikoff其他文献
Claude P Selitrennikoff的其他文献
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{{ truncateString('Claude P Selitrennikoff', 18)}}的其他基金
A novel recombinant vaccine against Cryptococcus.
一种针对隐球菌的新型重组疫苗。
- 批准号:
6841870 - 财政年份:2004
- 资助金额:
$ 10.2万 - 项目类别:
A novel yeast vaccine against Coccidioides Immitis
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6645740 - 财政年份:2003
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$ 10.2万 - 项目类别:
The glyoxylate cycle as a new target for antifungals
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6579674 - 财政年份:2003
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How is Cryptococcus resistant ot echinocandins?
隐球菌如何对棘白菌素产生耐药性?
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6746506 - 财政年份:2003
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6688368 - 财政年份:2003
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$ 10.2万 - 项目类别:
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隐球菌如何对棘白菌素产生耐药性?
- 批准号:
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