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Novel Therapeutics for Class B Protozoa

B 类原生动物的新疗法

基本信息

批准号：
7452689
负责人：
SHARON L REED
金额：
$ 130万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452689
关键词：
Active Sites Adverse effects Amebiasis Antiparasitic Agents Arginine Basic Science Biological Assay Canis familiaris Cathepsin E Cathepsins Cathepsins B Chagas Disease Charge Chemicals Chemistry Class Community Health Crystallization Crystallography Cyst Cysteine Cysteine Protease Cysteine Proteinase Inhibitors Data Development Disease Disease Outbreaks Drug Delivery Systems Drug Design Drug Kinetics Endopeptidases Entamoeba histolytica Enzymes Epidemic Family Fibroblasts Food Foundations Future Giardia Giardia lamblia Giardiasis Goals Grant Health Homologous Gene Human Imidazole Immune In Vitro Infection Ingestion Inhibitory Concentration 50 International Intestines Invasive K11777 Laboratories Lead Libraries Ligands Mammalian Cell Modeling Molecular Target Mus Osteoporosis Papain Parasites Parasitic Diseases Pathogenesis Peptide Hydrolases Personal Satisfaction Pharmaceutical Chemistry Pharmaceutical Preparations Pichia Play Positioning Attribute Primates Protozoa Recombinants Reporting Resistance Rodent Role SCID Mice Safety Screening procedure Series Specificity Standards of Weights and Measures Structure Structure-Activity Relationship Subgroup Synthesis Chemistry Testing Toxic effect Toxicity Tests Toxicology Translating Water Work Xenograft procedure base cathepsin K chemotherapy design divinyl sulfone drug development drug discovery excystation foodborne foodborne outbreak high throughput screening human disease improved in vitro Model in vivo in vivo Model inhibitor/antagonist monolayer mouse model novel novel therapeutics nutrition pre-clinical programs scaffold small molecule structural genomics waterborne

项目摘要

DESCRIPTION (provided by applicant): Entamoeba histolytica and Giardia lamblia are Class B protozoa, which are major causes of water- and foodborne epidemics worldwide. Identification of new molecular targets for drug development is key for future therapy as resistance to the main class of drugs, imidazoles, has been detected in both parasites. This proposal brings together the expertise and interdisciplinary efforts of four major laboratories to build on basic research on parasite pathogenesis for a focus on drug development. We have shown that cysteine proteinases are critical for invasion of E. histolytica and excystation of G. lamblia. Cathepsins are an attractive drug target as they have been well characterized biochemically and structurally and are the focus of large inhibitor libraries. EhCP1, one of two cysteine proteinases unique to E. histolytica, is undergoing crystallization studies under Dr. Van Voorhis. The enzyme's unique requirement for arginine in the P2 position, led to the synthesis of a lead small molecule inhibitor by Dr. Roush's group with an IC50 for EhCP1 of <25 nM and >10-fold specificity for the amebic enzyme vs. human cathepsin B. We will test the proof of priniciple that we can develop an inhibitor that is sensitive, nontoxic, and specific for the protozoal cathepsins. Dr. Roush's group will synthesize additional compounds with improved potency and specificity for the parasitic enzymes based on SAR data we have generated. The lead compounds will then undergo basic toxicity testing and efficacy in standard models for in vitro and in vivo amebic infection. We will leverage the findings of the initial crystallization studies of EhCP1 to a structural based drug discovery to guide medicinal chemistry. The active, recombinant enzyme of the next drug target, GICP2, has been expressed by Dr. McKerrow's group and the effect of inhibitors on excystation will be validated with Dr. Gillin. We will also identify other potential classes of inhibitors by high throughput screening of Dr. McKerrow's focused 4000 compound library. These studies will provide the basis to identify novel cathepsin inhibitors against amebic and giardial cathepsins with the potential to target other protozoal enzymes in the future. Relevance. These studies will focus on new drug targets for amoebiasis and giardiasis, important causes of food- and waterborne outbreaks, and may lead to the development of a new class of antiparasitic drugs.

描述（由申请人提供）：溶组织内阿米巴和兰氏贾第鞭毛虫是B类原虫，是世界范围内水和食源性流行病的主要原因。鉴定用于药物开发的新分子靶点是未来治疗的关键，因为在这两种寄生虫中已经检测到对主要类别的药物咪唑类的耐药性。该提案汇集了四个主要实验室的专业知识和跨学科努力，以寄生虫发病机制的基础研究为基础，重点关注药物开发。我们已经证明半胱氨酸蛋白酶是大肠杆菌入侵的关键。溶组织和脱囊G.兰布利亚。组织蛋白酶是一个有吸引力的药物靶标，因为它们已经在生物化学和结构上得到了很好的表征，并且是大型抑制剂文库的焦点。EhCP 1是大肠杆菌特有的两种半胱氨酸蛋白酶之一。正在货车沃里斯博士的指导下进行结晶研究。该酶在P2位置对精氨酸的独特需求，导致Dr. Jeneh的小组合成了一种先导小分子抑制剂，其对EhCP 1的IC 50是<25 nM and >阿米巴酶与人组织蛋白酶B特异性的10倍。我们将测试原理的证据，我们可以开发一种抑制剂，是敏感的，无毒的，并具体的原生动物组织蛋白酶。Dr. Bauh的团队将根据我们生成的SAR数据合成额外的化合物，这些化合物对寄生酶具有更好的效力和特异性。先导化合物随后将在体外和体内阿米巴感染的标准模型中进行基本毒性测试和功效测试。我们将利用EhCP1的初步结晶研究结果，以结构为基础的药物发现，以指导药物化学。下一个药物靶点GICP 2的活性重组酶已由McKerrow博士的小组表达，抑制剂对脱囊的影响将由Gillin博士验证。我们还将通过高通量筛选McKerrow博士的重点4000化合物库来确定其他潜在的抑制剂类别。这些研究将提供基础，以确定新的组织蛋白酶抑制剂对阿米巴和心血管组织蛋白酶的潜在目标其他原生动物的酶在未来。本案无关这些研究将侧重于阿米巴病和贾第虫病的新药物靶点，这是食物和水传播疾病暴发的重要原因，并可能导致一类新的抗寄生虫药物的开发。