Fumagillin Derivatives as Novel Antigiardiasis and Antiamebiasis Drugs

 描述(由申请人提供)：该项目专注于开发烟美西林类似物，以对抗标准治疗、抗贾第虫病和抗阿米巴病药物的失败。蓝氏贾第鞭毛虫和溶组织内阿米巴是高度传染性的寄生虫，会导致严重的腹泻疾病，导致世界各地贫困地区的许多苦难。所有标准护理药物都有不良副作用，贾第虫病治疗失败的频率约为20%，对于不耐受副作用的患者，只有少数药物可用于治疗阿米巴病。贾第鞭毛虫的耐药性已经成为一个令人担忧的问题，兰氏革兰氏菌和溶组织埃希氏菌的耐药性菌株可以很容易地在实验室培养出来。可用于治疗贾第鞭毛虫病和阿米巴病的药物只属于几个化学类别，主要是硝基咪唑和噻唑类。因为革兰氏杆菌对这类化合物的耐药性已经存在，它很可能会迅速发展为新的类成员。因此，新药开发项目应该把重点放在确定新的化学支架上。通过对批准的药物库进行化合物筛选，我们发现欧盟用于治疗免疫受损患者肠道微孢子虫病的孤儿药物伏马西林在体外高效杀灭贾第虫滋养体，并在感染小鼠中显示出比标准护理药物甲硝唑更好的疗效。此外，60年前，有报道称，伏马西林能有效治疗人类肠道阿米巴病。伏马西林是一种蛋氨酸氨基肽酶2抑制剂，这种酶还没有被用于抗贾第虫病和抗阿米巴病药物的开发。虽然烟青素被认为对治疗贾第鞭毛虫病和阿米巴病都有效，但它有两个风险，潜在的毒性和高温和湿度不稳定。为了优化药物性能，我们将合成不太容易在储存和代谢降解过程中受到化学不稳定性影响的伏马西林衍生物，同时降低对肠道上皮屏障的通透性，以防止潜在的毒性影响。将在贾第虫病和阿米巴病小鼠模型中研究新的蛋氨酸氨基肽酶2抑制剂，这些药物将在甲硝唑敏感和甲硝唑耐药的蓝氏菌和/或溶组织革兰氏菌菌株中显示良好的效力，并提供更高的稳定性和降低对Caco-2单层的通透性。最有效的化合物的药代动力学和毒性曲线将在小鼠身上进行测定，以确认体外渗透性的降低会导致宿主生物利用度和体内毒性的降低。该项目的结果将是1-2种化合物，与母药福马西林相比，具有更好的毒性和稳定性，对贾第鞭毛虫病和/或阿米巴病有效。这些化合物将为支持IND的研究做好准备。

 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.