Development of PTLS-209 for treatment for giardiasis

项目总结： 该项目的重点是开发治疗方法，以对抗贾第鞭毛虫病对标准护理药物的耐药性。 蓝氏贾第鞭毛虫是一种高度传染性的水媒寄生虫，会导致严重腹泻。当前抗贾第鞭毛虫病药物 大约20%的病例失败，而且它们都有令人不快的副作用。此外，耐药的兰布里亚革兰氏菌 菌株很容易在实验室中培养，增加了这种B类生物恐怖主义生物的风险。 在发展中国家，贾第鞭毛虫病的慢性感染和缺乏治疗导致营养不良、生长 儿童发育迟缓和死亡。因此，贾第鞭毛虫病的流行深刻地影响着全球健康， 世界卫生组织已将贾第鞭毛虫病列入其被忽视的疾病倡议。 我们的合作者和NCATS/NIH的调查人员通过筛选 批准的药品资料库。福马西林通过抑制MetAP2高效杀灭贾第鞭毛虫滋养体。它有 在活体小鼠模型中也显示出极好的疗效；然而，它有两个缺点：高温和湿度 不稳定，以及对人类的潜在毒性。这些责任阻碍了伏马西林的进一步发展。 我们在销售线索优化过程中解决了这些问题，并确定了PTLS-209，它具有高性能 MetAP2的效力、低生物利用度、改善疗效和增强稳定性。因此，PTLS-209具有理想的 是治疗贾第鞭毛虫病，尤其是耐药贾第鞭毛虫病的有效和安全的肠道靶向药物 贾第鞭毛虫病。 可用于治疗贾第鞭毛虫病的药物只属于几个化学类别，主要是 硝基咪唑、噻唑和苯并咪唑。革兰氏阴性杆菌对这些细菌的耐药性都已经存在。 化合物的类别。目前用于治疗贾第鞭毛虫病的药物都不作用于MetAP2酶。因此， PTLS-209，一种烟曲西林类似物，将不会受到目前导致 治疗失败。 PTLS-209具有极好的安全性，而其他烟青素类类似物Beloranib、ZGN-1061和 ZGN-1258在临床前研究和临床试验中显示出不良反应。请注意，这些类比是 皮下给药，而PTLS-209是口服的，口服生物利用度很低 在小鼠身上(这可能是其毒性低的原因)。为了及早降低风险，我们采用了“失败” “早、败、便宜”的做法。在我们的SBIR阶段，我们提出了两个关键测试来评估这些毒性问题 I快速通道应用程序的一部分。一旦我们达到第一阶段的里程碑，我们将继续支持IND 研究以确保PTLS-209具有成功治疗贾第鞭毛虫病的所有属性，并将提交 IND应用程序。

Project Summary: This project focuses on the development of treatment to combat giardiasis resistance to standard care drugs. Giardia lamblia is a highly infective waterborne parasite that causes severe diarrhea. Current antigiardiasis drugs fail in about 20% of cases, and they all have undesirable side effects. Additionally, drug-resistant G. lamblia strains can be readily raised in the laboratory, increasing the risk of this category B bioterrorism organism. Chronic infection of giardiasis and lack of treatment in developing countries lead to malnutrition, growth retardation in children, and death. Thus, the prevalence of giardiasis impacts global health profoundly, and the World Health Organization has included giardiasis in its Neglected Diseases Initiative. Our collaborators and NCATS/NIH investigators identified fumagillin as a lead compound through screening an approved drug library. Fumagillin kills Giardia trophozoites in vitro with high potency via MetAP2 inhibition. It has also shown excellent efficacy in an in vivo mouse model; however, it has two liabilities: heat and humidity instability, as well as potential toxicity in humans. These liabilities hamper the further development of fumagillin. We addressed these issues during our lead optimization process and identified PTLS-209, which has high potency for MetAP2, low bioavailability, improved efficacy, and enhanced stability. Thus, PTLS-209 has the ideal attributes to be an effective and safe intestinal targeting drug for treating giardiasis, particularly drug-resistant giardiasis. The arsenal of drugs available for treating giardiasis belongs to only a few chemical classes, primarily nitroimidazoles, thiazolides, and benzimidazoles. G. lamblia drug resistance already exists for each of these classes of compounds. None of the currently used drugs to treat giardiasis act on the MetAP2 enzyme. Thus, PTLS-209, a fumagillin analog, will not be subject to the current drug resistance mechanisms that result in treatment failures. PTLS-209 has an excellent safety profile, while other analogs of the fumagillin class, beloranib, ZGN-1061, and ZGN-1258, have shown adverse effects in preclinical studies and clinical trials. Note that these analogs were administered subcutaneously, whereas PTLS-209 is administered orally and has a very low oral bioavailability in mice (which may be the cause of its low toxicity). In order to mitigate the risks early, we have adopted the “Fail Early, Fail Cheap” approach. We propose two critical tests to evaluate these toxicity concerns in our SBIR Phase I portion of the Fast-Track application. Once we meet our Phase I milestones, we will continue IND-enabling studies to ensure that PTLS-209 has all the attributes to be a successful treatment for giardiasis and will file an IND application.