Functional Genomic Approach to Macrofilaricide Discovery

发现大丝虫杀剂的功能基因组方法

• 批准号: 7490901
• 负责人: James P. McCarter
• 金额: $ 28.42万
• 依托单位: DIVERGENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490901
• 关键词: Adolescent; Adult; Affect; Albendazole; Animal Model; Anthelmintics; Area; Biochemical; Bioinformatics; Biological; Biology; Brugia; Brugia malayi; Caenorhabditis elegans; Cessation of life; Chemicals; Cholesterol; Class; Clinical; Clinical Trials; Collaborations; Collection; Complement; Country; Development; Diethylcarbamazine; Disease; Disease Clusterings; Dose; Drug Kinetics; Drug resistance; Economic Burden; Economics; Elephantiasis; Ensure; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Esters; Expressed Sequence Tags; Face; Family; Female; Filarial Elephantiases; Foundations; Gene Targeting; Generations; Genes; Genomics; Genus Wuchereria; Ghana; Goals; Guanosine Monophosphate; Health; Human; In Vitro; International; Investments; Ivermectin; Larva; Lead; Methods; Microfilaria; Molecular Target; Monitor; Morbidity - disease rate; Morphology; Nematoda; Numbers; Ocular Onchocerciasis; Onchocerca volvulus; Onchocerciasis; Orthologous Gene; Outcome; Oxidoreductase; Parasites; Parasitic nematode; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phylogenetic Analysis; Population; Production; Proteins; Public Health; Publishing; RNA Interference; Range; Recombinants; Reproduction; Research; Resistance; Risk; Rodent Model; Role; Safety; Screening Result; Screening procedure; Staging; Structure; Techniques; Testing; Time; Treatment Protocols; Validation; Work; World Health Organization; assay development; base; blind; chemical synthesis; cheminformatics; clinically significant; comparative; cytotoxicity; data modeling; disability; filaria; fluvastatin; functional genomics; genome sequencing; glutaryl coA; health economics; high throughput screening; in vitro Assay; in vivo; inhibitor/antagonist; isoprenoid; killings; molecular modeling; novel; pre-clinical; pressure; programs; small molecule; small molecule libraries; success

DESCRIPTION (provided by applicant): Parasitic filarial nematodes causing lymphatic filariasis and river blindness (onchocerciasis), infect over 140 million people with up to one billion at risk in at least 80 countries and territories. Lymphatic filariasis (caused by Wuchereria and Brugia species) creates an enormous health and economic burden within affected areas and is ranked as the second leading cause of long-term disability. In 2000, international groups including the World Health Organization launched an initiative to eliminate lymphatic filariasis by conducting mass drug administrations. Although the compounds available for this program (ivermectin, albendazole, diethylcarbamazine) are effective at killing larvae (microfilariae), the adult reservoir of parasites (macrofilariae) survive and can remain in the body for a decade. In addition, the extreme selective pressure of mass treatment has lead to recent signs of parasite drug resistance. Similar challenges face the campaigns to reduce onchocerciasis with ivermectin. The long-term objective of this project is to develop new compounds with 'macrofilaricidal' activity that are desperately needed to complement the current regimens. During Phase I efforts, bioinformatic filters and functional genomic (RNAi) data from the model nematode Caenorhabitis elegans and the filarial parasite Brugia malayi were utilized to successfully identify and prioritize a small set of molecular targets predicted to be critical for macrofilarial survival. In addition, as a prelude to Phase II research, compounds previously demonstrated to possess nematicidal activity at Divergence were tested against Brugia spp. in vitro, with some compounds showing promising macrofilaricidal effects. In the current research, two well-characterized and essential enzymes from a filarial nematode biosynthetic pathway will be expressed and inhibitors identified through a combination of high-throughput chemical library screening and targeted cheminformatic approaches. The best hits will be evaluated against adult B. malayi and in vitro and assayed for mammalian cytotoxicity and microsomal stability. Finally, the most promising compounds will progress into rodent model trials of lymphatic filariasis. The expected outcome of this work is the identification of lead molecules that demonstrate macrofilaricidal activity within animal models. In collaboration with agencies that have demonstrated a commitment to global health equity (such as the Gates Foundation or WHO), Phase III efforts will focus on the initiation of clinical trials in humans--with the ultimate goal of eliminating the human health burden of filarial diseases. (Relevance to public health) Parasitic nematodes (roundworms) currently infect over 1 billion people globally, causing severe morbidity and considerable economic losses. This project is structured to identify desperately needed drugs to combat filarial nematodes, which constitute the most significant of the human tropical cluster diseases. Filarial parasites cause some of the more pernicious nematode-borne diseases known (elephantiasis and river blindness).

描述（由申请人提供）：引起淋巴丝虫病和河盲症（盘尾丝虫病）的寄生性丝虫线虫在至少80个国家和地区感染超过1.4亿人，风险高达10亿人。淋巴丝虫病（由吴策线虫属和布鲁贾属物种引起）在受影响地区造成巨大的健康和经济负担，被列为长期残疾的第二大原因。2000年，包括世界卫生组织在内的国际组织发起了一项通过大规模药物管理来消除淋巴丝虫病的倡议。尽管该方案可用的化合物（伊维菌素、阿苯达唑、乙胺嗪）对杀灭幼虫（微丝蚴）有效，但寄生虫（微丝蚴）的成虫宿主存活下来，并可在体内停留十年。此外，大规模治疗的极端选择压力导致最近出现寄生虫抗药性的迹象。用伊维菌素减少盘尾丝虫病的运动也面临类似的挑战。该项目的长期目标是开发具有“杀大型丝虫”活性的新化合物，以补充当前的治疗方案。在第一阶段的工作中，利用来自线虫模型秀丽隐杆线虫和丝虫寄生虫马来丝虫的生物信息学过滤器和功能基因组（RNAi）数据，成功地识别和优先考虑了一小组预测对巨丝虫生存至关重要的分子靶标。此外，作为II期研究的前奏，对先前在Divergence证明具有杀线虫活性的化合物进行了针对布氏丝虫属的测试。在体外，一些化合物显示出有希望的杀微丝蚴作用。在目前的研究中，两个充分表征和必要的酶从丝虫线虫生物合成途径将表达和抑制剂通过高通量化学文库筛选和有针对性的化学信息学方法相结合的确定。将针对成人B评价最佳命中。Malayi和体外培养，并测定哺乳动物细胞毒性和微粒体稳定性。最后，最有希望的化合物将进入淋巴丝虫病的啮齿动物模型试验。这项工作的预期成果是鉴定在动物模型中表现出杀巨丝虫活性的铅分子。第三阶段的工作将与已表明致力于全球卫生公平的机构（如盖茨基金会或世卫组织）合作，重点是启动人体临床试验，最终目标是消除丝虫病对人类健康造成的负担。（与公共卫生的相关性）寄生线虫（蛔虫）目前感染全球超过10亿人，造成严重的发病率和巨大的经济损失。该项目旨在确定迫切需要的药物，以防治构成人类最严重热带集群疾病的丝虫病。丝虫寄生虫引起一些已知的更致命的线虫传播疾病（象皮病和河盲症）。