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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.

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