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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：
9089862
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/9089862
关键词：
Adverse effects Affect Amebiasis Amebic colitis Biological Assay Biological Availability Body Weight decreased Caco-2 Cells 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 Health Heating Human Humidity Immune In Vitro Infection 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 novel therapeutics pathogen prevent 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（由申请人提供）：该项目的重点是开发夫马洁林类似物，以对抗标准护理抗贾第鞭毛虫病和抗阿米巴病药物的失败。贾第鞭毛虫和溶组织内阿米巴是高度传染性的寄生虫，可引起严重的腹泻病，给全世界贫困地区带来巨大痛苦。所有标准治疗药物都有不良副作用，贾第鞭毛虫病治疗失败的概率约为 20%，而且只有少数药物可用于治疗不能耐受副作用的患者的阿米巴病。贾第鞭毛虫耐药性已成为一个问题，兰氏贾第鞭毛虫和溶组织内贾第鞭毛虫耐药菌株可以在实验室中轻易培养。可用于治疗贾第虫病和阿米巴病的药物仅属于少数化学类别，主要是硝基咪唑和噻唑烷类。由于兰氏杆菌对这些类别的化合物已经存在耐药性，因此它很可能会迅速发展到新的类别成员。因此，新药开发项目应侧重于识别新的化学支架。通过对已批准药物库的化合物筛选，我们发现夫马洁林（欧盟用于治疗免疫受损患者肠道微孢子虫病的孤儿药）在体外高效杀死贾第鞭毛虫滋养体，并且与标准治疗药物甲硝唑相比，在感染小鼠中表现出更优异的疗效。而且，60年前，烟曲霉素就被报道可以有效治愈人类肠道阿米巴病。 Fumagillin 是一种蛋氨酸氨基肽酶 2 抑制剂，这种酶尚未成为抗贾第鞭毛虫病和抗阿米巴病药物开发的目标。虽然夫马洁林有望有效治疗贾第鞭毛虫病和阿米巴病，但它有两个缺点：潜在毒性以及热和湿度不稳定。为了优化药物特性，我们将合成在储存和代谢降解过程中不易出现化学不稳定的夫马洁林衍生物，同时降低肠上皮屏障的渗透性，以防止潜在的毒性作用。新型甲硫氨酸氨基肽酶 2 抑制剂将在甲硝唑反应性和甲硝唑耐药性 G. Lamblia 和/或 E. histolytica 菌株中显示出良好的效力，并在贾第虫病和阿米巴病小鼠模型中进行体内研究，提高 Caco-2 单层的稳定性并降低渗透性。最有效的化合物的药代动力学和毒性特征将在小鼠中进行测定，以确认体外渗透性降低导致宿主体内生物利用度和毒性降低。该项目的成果将是 1-2 种对贾第鞭毛虫病和/或阿米巴病有效的化合物，与母体药物夫马洁林相比，具有更优异的毒性和稳定性。这些化合物将为 IND 研究做好准备。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cryo-EM structure of the ancient eukaryotic ribosome from the human parasite Giardia lamblia.

DOI：
10.1093/nar/gkac046
发表时间：
2022-02-22
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Hiregange DG;Rivalta A;Bose T;Breiner-Goldstein E;Samiya S;Cimicata G;Kulakova L;Zimmerman E;Bashan A;Herzberg O;Yonath A
通讯作者：
Yonath A