Fumagillin Derivatives as Novel Antigiardiasis and Antiamebiasis Drugs

夫马洁林衍生物作为新型抗贾第鞭毛虫病和抗阿米巴病药物

基本信息

批准号：
8960227
负责人：
OSNAT HERZBERG
金额：
$ 20.9万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960227
关键词：
Adverse effects Affect Amebiasis Amebic colitis Biological Assay Biological Availability Body Weight decreased Caco-2 Cells Caring Cell Survival Cessation of life Chemicals Data Development Disease Drug Kinetics Drug Targeting Drug resistance Drug usage Employee Strikes Entamoeba histolytica Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epithelial Epithelial Cells Epoxy Compounds Equilibrium Esters European Union Evaluation Exhibits Failure Frequencies Generations Giardia Giardia lamblia Giardiasis Goals Heating Human Humidity Immune In Vitro Infection Inhibitory Concentration 50 Intestinal Absorption Intestines Invaded Laboratories Lead Libraries Mammalian Cell Metabolic Methods Metronidazole Metronidazole resistance Microsporidiosis Mus Nitroimidazoles Orphan Drugs Outcome Parasites Parents Patients Permeability Pharmaceutical Preparations Phase Platelet Count measurement Poverty Production Property Recurrent disease Reporting Resistance Side Tail Temperature Testing Therapeutic Toxic effect Treatment Failure absorption alternative treatment analog combat comparative drug candidate drug development economic impact esterase fumagillin improved in vivo inhibitor/antagonist killings member methionine aminopeptidase 2 monolayer mouse model novel pathogen prevent public health relevance resistance mechanism resistant strain safety study scaffold scale up screening socioeconomics standard care

项目摘要

DESCRIPTION (provided by applicant): This project focuses on the development of fumagillin analogs to combat failures of standard care antigiardiasis and antiamebiasis drugs. Giardia lamblia and Entamoeba histolytica are highly infective parasites that cause severe diarrheal diseases, leading to much suffering in poverty stricken regions worldwide. All standard care drugs have undesirable side effect, giardiasis treatment fails at a frequency of ~20% cases, and there are only a few drugs available to treat amebiasis for patients that do not tolerate the side effects. Giardia drug resistance has become a concern, and G. lamblia and E. histolytica drug-resistant strains can be readily raised in the laboratory. The arsenal of drugs available for treating giardiasis and amebiasis belong to only a few chemical classes, primarily nitroimidazoles and thiazolides. Because G. lamblia drug resistance already exists for these classes of compounds, it is likely to progress rapidly to new class members. Thus, new drug development projects should focus on identifying new chemical scaffolds. Using compound screening of an approved drug library, we discovered that fumagillin, an orphan drug used in the European Union to treat intestinal microsporidiosis in immune compromised patients, kills Giardia trophozoites in vitro with high potency and exhibits superior efficacy in infected mice compared with the standard care drug, metronidazole. Moreover, 60 years ago, fumagillin was reported to effectively cure human intestinal amebiasis. Fumagillin is a methionine aminopeptidase 2 inhibitor, an enzyme that has not been targeted yet for antigiardiasis and antiamebiasis drug development. While fumagillin is expected to be effective in curing both giardiasis and amebiasis it has two liabilities, potential toxicity and heat and humidity instabiliy. To optimize drug properties, we will synthesize fumagillin derivatives that are less liable to chemical instability on storage and metabolic degradation, and concomitantly have reduced permeability through the intestinal epithelial barrier to prevent potential toxic effects. New methionine aminopeptidase 2 inhibitors that will show good potency in metronidazole-responsive and metronidazole-resistant G. lamblia and/or E. histolytica strains as well as provide increased stability and reduced permeability across Caco-2 monolayers will be investigated in vivo in giardiasis and amebiasis mouse models. The pharmacokinetics and toxicity profiles of the most efficacious compounds will be determined in mice to confirm that the reduced in vitro permeability leads to reduced host bioavailability and toxicity in vivo. The outcome of the project will be 1-2 compounds efficacious against giardiasis and/or amebiasis with superior toxicity and stability properties compared with the parent drug, fumagillin. These compounds will be ready for IND-enabling studies.

描述（由适用提供）：该项目的重点是开发烟蛋白类似物，以打击标准护理抗胃菌病和抗虫病药物的失败。贾第鞭毛虫兰布利亚（Giardia Lamblia）和entamoeba Histolictica是高度感染的寄生虫，引起严重的腹泻疾病，导致全球贫困地区的痛苦遭受巨大苦难。所有标准护理药物均具有不良的副作用，贾第鞭毛疾病的治疗频率约为20％，并且只有少数药物可用于治疗不耐受副作用的患者的amebiasis。贾第鞭毛虫的耐药性已成为一个关注点，兰布利亚省和E. histolictica抗药性菌株很容易在实验室中升高。可用于治疗贾第鞭毛疾病和阿米巴病的药物的武器库仅属于几种化学类别，原发性硝基咪唑和噻唑烷。由于G. lamblia的耐药性已经存在于这些类型的化合物中，因此可能会迅速发展为新的班级成员。这是新的药物开发项目应着重于确定新的化学脚手架。使用批准的药物库的化合物筛选，我们发现富马吉林是一种欧盟中用于治疗免疫损害患者肠道微孢子虫病的孤儿药，杀死了贾尔迪亚滋养体的体外，具有较高的效力，与标准护理药物，甲m甲甲虫相比，在感染的小鼠中表现出较高的效率，并且在感染的小鼠中表现出较高的效率。此外，据报道，60年前，富马吉林有效地治愈了人类肠道症。富马吉蛋白是一种蛋氨酸氨肽酶2抑制剂，这是一种尚未靶向抗胃菌病和抗蛋白症药物的酶。虽然富马吉林有效地治愈贾洲菌和阿米巴病有效，但它具有两种责任，潜在的毒性，热量和湿度。为了优化药物特性，我们将合成对化学不稳定性的富马吉林衍生物的储存和代谢降解，并同时通过肠上皮屏障降低了渗透率，以防止潜在的毒性作用。新的甲二氨酸氨肽酶2抑制剂将在甲硝唑反应和甲硝唑耐药的G. lamblia和/或E. histolodictica菌株中表现出良好的效力，并提供了稳定性，并提供了提高的稳定性，并降低了CACO-2单层的渗透率，将在Giardiasis和Amebiase somebiase in vivo中进行研究。最有效化合物的药代动力学和毒性谱将在小鼠中确定，以确认降低的体外通透性会导致体内宿主生物利用度和毒性降低。与母体药物富马吉林相比，该项目的结果将是针对贾第鞭毛疾病和/或阿米巴病有效的1-2化合物。这些化合物将准备好进行辅助研究。