Targeting a New Therapy for Trypanosomatids

项目摘要：发展中国家有10亿人面临利什曼病的风险，利什曼病 每年有近200万人毁容或死亡。利什曼病及相关疾病的治疗现状 寄生虫病、人类非洲锥虫病和恰加斯病效果差、毒性大。不是 可以治疗这三种传染病的药物都是可用的。我们的长期目标是开发一种 治疗锥虫感染的有效新药。通过筛选一种小分子化合物集合来对抗 亚马逊利什曼原虫，我们鉴定了一种新的具有有效和选择性抗锥虫的支架。 活动。我们最有效的类似物对无性无鞭毛虫的EC50为15 NM(50 NM) 胞内无鞭毛体)，选择性指数为49。我们的化学系列具有广泛的功效范围，并且 几个类似物的效力、选择性、溶解度和稳定性指数超过了已公布的进展标准。 我们的数据表明，这些化合物促进微管蛋白聚合，这将是一种新的机制 针对抗原虫药物的行动。这些研究的目的是确定一种晚期铅化合物与 皮肤利什曼病治疗的发展潜力。在目标1中，我们将定义分子靶标 在我们的院子里。我们将使用遗传和化学生物学方法来表征它与 并确定相关的结合伙伴。在目标2中，我们将用体外方法鉴定抗利什曼类化合物 和体内疗效。化合物将从有效的命中进展到早期线索，然后是如果它们相遇则是晚期线索 已公布的标准。我们将使用迭代药物化学来改善疗效和化学特性 一种方法，其中合成策略通过包括体外效力测试的级联来提供信息 抗寄生虫和微管蛋白，用细胞毒性试验评估选择性，并表征ADME 性质(如代谢稳定性、水溶度和血浆稳定性)和药代动力学(PK)。至 早期先导的进展，化合物必须在概念验证小鼠模型中证明有效性 皮肤利什曼病。为了发展到晚期，化合物必须治愈由小组造成的小鼠损伤 皮肤利什曼原虫的种类。我们最有希望的线索将进行安全药理学研究(例如， CYP抑制、Ames测试和CEREP面板)。我们还将确定我们的销售线索的产品配置文件 未来发展与人本管理。在目标3中，我们将通过筛选以下项目获得备用脚手架 影响微管蛋白动力学的抗利什曼药物。我们将确定寄生虫的命中选择性，而不是 并测试最有效和最具选择性的微管蛋白效应器对亚马孙乳杆菌的活性。 在目标完成后，我们将确定一种用于皮肤利什曼病的晚期先导化合物和其他 备份候选人以供进一步评估。我们的研究具有重大意义和创新性，因为它将增加 对目前有限的研发管道具有新的作用机制的化合物 可用于抗击这些被忽视的热带疾病。

PROJECT SUMMARY: One billion people in the developing world are at risk for leishmaniasis, which disfigures or kills nearly 2 million people each year. Current therapies for leishmaniasis and the related parasitic diseases human African trypanosomiasis and Chagas disease are poorly effective and toxic. No drugs that can treat all three of these infectious diseases are available. Our long-term goal is to develop an effective new drug for trypanosomatid infections. By screening a small molecule compound collection against Leishmania amazonensis, we have identified a new scaffold with potent and selective anti-trypanosomatid activity. Our most potent analog has an EC50 of 15 nM against L. amazonensis axenic amastigotes (50 nM for intracellular amastigotes) and a selectivity index of 49. Our chemical series has a broad efficacy range, and several analogs have potency, selectivity, solubility, and stability indices over published advancement criteria. Our data suggest that these compounds facilitate tubulin polymerization, which would be a novel mechanism of action for antiprotozoal drugs. The objective of these studies is to identify a late lead compound with the potential to advance for the treatment of cutaneous leishmaniasis. In Aim 1, we will define the molecular target of our compound. We will use genetic and chemical biology approaches to characterize its interaction with tubulin and identify relevant binding partners. In Aim 2, we will identify antileishmanial compounds with in vitro and in vivo efficacy. Compounds will progress from validated hits to early leads and then late leads if they meet published criteria. We will improve efficacy and chemical properties using an iterative medicinal chemistry approach in which the synthesis strategy is informed by a cascade that includes testing for in vitro potency against parasites and tubulin, assessing selectivity with cytotoxicity assays, and characterizing ADME properties (e.g., metabolic stability, aqueous solubility and plasma stability) and pharmacokinetics (PK). To progress to early leads, compounds must demonstrate efficacy in a proof-of-concept mouse model for cutaneous leishmaniasis. To progress to late leads, compounds must cure lesions in mice caused by a panel of cutaneous Leishmania species. Our most promising leads will undergo safety pharmacology studies (e.g., CYP inhibition, Ames testing, and CEREP panels). We will also determine the product profile of our leads for future development and human administration. In Aim 3, we will obtain backup scaffolds by screening for antileishmanial agents that affect tubulin dynamics. We will determine hit selectivity for parasite rather than mammalian tubulin and test the most potent and selective tubulin effectors for activity against L. amazonensis. Upon Aim completion, we will have identified a late lead compound for cutaneous leishmaniasis and additional backup candidates for further evaluation. Our research is significant and innovative because it would add compounds with a novel mechanism of action to the limited research and development pipeline that is currently available to combat these neglected tropical diseases.