Fumagillin Derivatives as Novel Antigiardiasis and Antiamebiasis Drugs

 描述（由申请人提供）：该项目的重点是开发烟曲霉素类似物，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，它们会引起严重的疟疾，给全世界贫困地区带来许多痛苦。所有标准治疗药物都有不良副作用，贾第虫病治疗失败的频率约为20%，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。贾第鞭毛虫的耐药性已成为一个问题，G。lamblia和E.溶组织菌耐药菌株可以在实验室中容易地培养。可用于治疗贾第虫病和阿米巴病的药物库仅属于少数化学类别，主要是硝基咪唑类和噻唑类。因为G.对于这些种类的化合物，已经存在兰氏杆菌耐药性，它可能迅速发展为新的种类成员。因此，新药开发项目应侧重于确定新的化学支架。使用批准的药物库的化合物筛选，我们发现，烟曲霉素，在欧盟用于治疗免疫功能低下患者的肠道微孢子虫病的孤儿药，杀死贾第虫滋养体在体外具有高效力，并表现出上级疗效在感染的小鼠相比，标准治疗药物甲硝唑。而且，60年前，烟曲霉素被报道可以有效地治愈人类肠道阿米巴病。烟曲霉素是一种甲硫氨酸氨基肽酶2抑制剂，这种酶尚未成为抗贾第虫病和抗阿米巴病药物开发的靶点。烟曲霉素对贾第鞭毛虫病和阿米巴病都有疗效，但它有两个缺点，即潜在的毒性和对热和湿度的不稳定性。为了优化药物特性，我们将合成烟曲霉素衍生物，其在储存和代谢降解时不易发生化学不稳定性，并且同时具有降低的通过肠上皮屏障的渗透性以防止潜在的毒性作用。新的甲硫氨酸氨基肽酶2抑制剂，将显示良好的效力，在甲硝唑敏感和甲硝唑耐药G。lamblia和/或E.将在贾第鞭毛虫病和阿米巴病小鼠模型中体内研究溶组织菌株以及提供增加的稳定性和降低的穿过Caco-2单层的渗透性。将在小鼠中测定最有效化合物的药代动力学和毒性特征，以证实体外渗透性降低导致体内宿主生物利用度和毒性降低。该项目的结果将是1-2种有效对抗贾第鞭毛虫病和/或阿米巴病的化合物，与母体药物烟曲霉素相比具有上级毒性和稳定性。这些化合物将准备用于IND使能研究。

 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.