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， 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、非洲锥虫病和南美锥虫病疗效差，而且有毒。没有 可以治疗所有这三种传染病的药物都是可用的。我们的长期目标是发展一个 治疗锥虫感染有效新药。通过筛选小分子化合物集合， 利什曼原虫亚马逊，我们已经确定了一个新的支架与有效的和选择性的抗锥虫 活动我们最有效的类似物对L的EC 50为15 nM。亚马逊无鞭毛体（50 nM， 细胞内无鞭毛体）和选择性指数为49。我们的化学品系列具有广泛的功效范围， 几种类似物的效力、选择性、溶解度和稳定性指数超过了公开的进展标准。 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， 抗原生动物药物的作用。这些研究的目的是确定一种晚期先导化合物， 潜在的皮肤利什曼病的治疗进展。在目标1中，我们将定义分子靶标 我们的化合物。我们将使用遗传和化学生物学方法来表征其与 微管蛋白并鉴定相关的结合伴侣。在目标2中，我们将在体外鉴定抗利什曼原虫化合物， 和体内功效。化合物将从经验证的命中进展到早期线索，然后如果它们满足，则是晚期线索 公布的标准。我们将使用迭代的药物化学来提高疗效和化学特性 通过级联（包括体外效价检测）了解合成策略的方法 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 属性（例如，代谢稳定性、水溶性和血浆稳定性）和药代动力学（PK）。到 为了向早期先导化合物发展，化合物必须在概念验证小鼠模型中证明其功效， 皮肤黑热病要发展到晚期，化合物必须治愈由一组药物引起的小鼠病变。 皮肤利什曼原虫物种。我们最有前途的线索将进行安全药理学研究（例如， β-内酰胺酶抑制、艾姆斯试验和CEREP板）。我们还将确定潜在客户的产品概况， 未来的发展和人类管理。在目标3中，我们将通过筛选 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， 哺乳动物微管蛋白，并测试最有效和选择性的微管蛋白效应物对L.亚马逊河。 目标完成后，我们将确定一种治疗皮肤利什曼病的晚期先导化合物， 后备候选人以供进一步评估。我们的研究是重要的和创新的，因为它将增加 具有新的作用机制的化合物的有限的研究和开发管道，目前 来对抗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.