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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：
7804552
负责人：
SHARON L REED
金额：
$ 138.06万
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/7804552
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 Community Health Crystallization Crystallography Cyst Cysteine Cysteine Protease Cysteine Proteinase Inhibitors Data Development Disease Disease Outbreaks Drug Delivery Systems Drug Design Drug Kinetics Entamoeba histolytica Enzymes Epidemic Family Fibroblasts Food Foundations Future Giardia Giardia lamblia Giardiasis Goals Grant Homologous Gene Human Imidazole Immune In Vitro Infection Ingestion Inhibitory Concentration 50 International Intestines Laboratories Lead Libraries Ligands Mammalian Cell Modeling Molecular Target Mus Osteoporosis Papain Parasites Parasitic Diseases Pathogenesis Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pichia Play Positioning Attribute Primates Protozoa Recombinants Reporting Resistance Rodent Role SCID Mice Safety Screening procedure Series Specificity 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 global health high throughput screening human disease improved in vitro Model in vivo in vivo Model inhibitor/antagonist meetings monolayer mouse model novel novel therapeutics nutrition pre-clinical programs safety study 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)：溶组织内阿米巴和蓝氏贾第鞭毛虫是B类原生动物，是全世界水源性和食源性流行病的主要原因。由于在两种寄生虫中都检测到了对主要药物咪唑类药物的耐药性，识别药物开发的新分子靶点是未来治疗的关键。这项建议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重点，专注于药物开发。我们的研究表明，半胱氨酸蛋白酶在溶组织埃希氏菌的入侵和兰氏革兰氏菌的清除过程中起着关键作用。组织蛋白是一个很有吸引力的药物靶点，因为它们在生化和结构上都有很好的特征，是大型抑制剂库中的焦点。EhCP1是溶组织肠杆菌特有的两种半胱氨酸蛋白酶之一，目前正在范·沃里斯博士的指导下进行结晶研究。这种酶对P2位精氨酸的独特要求，导致了Roush博士的团队合成了一种领先的小分子抑制剂，对EhCP1的IC50为25 NM，对阿米巴酶和人组织蛋白酶B的特异性为10倍。我们将测试原理证明，我们可以开发出一种敏感、无毒和针对原生动物组织蛋白酶的抑制剂。Roush博士的团队将根据我们生成的SAR数据合成更多的化合物，这些化合物对寄生酶的效力和特异性都有所提高。然后，先导化合物将在体外和体内阿米巴感染的标准模型中进行基本的毒性测试和有效性测试。我们将利用EhCP1的初步结晶研究结果来进行基于结构的药物发现，以指导药物化学。McKerrow博士的团队已经表达了下一个药物靶标GICP2的活性重组酶，抑制剂对Exystation的影响将与Glin博士一起验证。我们还将通过对McKerrow博士专注的4000化合物文库进行高通量筛选来确定其他潜在的抑制剂类别。这些研究将为发现针对阿米巴和贾第鞭毛虫组织蛋白的新型组织酶抑制剂提供基础，并有可能在未来针对其他原虫酶。关联性。这些研究将集中于阿米巴病和贾第鞭毛虫病的新药靶点，这是导致食物和水传播疫情的重要原因，并可能导致开发一类新的抗寄生虫药物。