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）： Entamoeba Hissolytica和Lamblia是B级原生动物，这是全球水和食源性流行病的主要原因。在两种寄生虫中都发现了对药物开发的新分子靶标的鉴定是对未来治疗的关键，因为对主要类别的药物，咪唑却是对主要治疗的抗药性。该提案汇集了四个主要实验室的专业知识和跨学科努力，以基于寄生虫发病机理的基础研究，以关注药物开发。我们已经表明，半胱氨酸蛋白酶对于浸润性大肠分泌性大肠杆菌和lamblia的脱囊膜至关重要。组织蛋白酶是一个有吸引力的药物靶标，因为它们在生化和结构上都具有很好的特征，并且是大型抑制剂文库的重点。 EHCP1是溶血性大肠杆菌特有的两种半胱氨酸蛋白酶之一，正在范沃尔博士下进行结晶研究。该酶在P2位置对精氨酸的独特需求，导致Roush博士的组与<25 nm的EHCP1的IC50合成铅小分子抑制剂，而Amebic酶的EHCP1的eHCP1则是10倍。组织蛋白酶。 Roush博士的小组将根据我们生成的SAR数据合成其他化合物，对寄生酶的效力和特异性提高。然后，铅化合物将在体外和体内占体感染的标准模型中接受基本毒性测试和功效。我们将利用EHCP1最初结晶研究的发现，以指导药物化学。下一个药物靶标GICP2的主动重组酶已由McKerrow博士的组表达，抑制剂对ExcyStation的影响将得到Gillin博士的验证。我们还将通过对McKerrow博士重点的4000复合库的高吞吐量筛选来确定其他潜在的抑制剂类别。这些研究将提供基础，以鉴定针对阿米比克和贾第鞭毛虫组织蛋白酶的新型组织蛋白酶抑制剂，以便将来靶向其他原生动物酶。关联。这些研究将集中在新药靶标的阿莫哈病和贾第鞭毛疾病，重要原因是食物和水源性疫情的重要原因，并可能导致新的抗寄生虫药物的发展。