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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：
7622064
负责人：
SHARON L REED
金额：
$ 137.19万
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/7622064
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 Health 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 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）：