Targeting a New Therapy for Trypanosomatids

针对锥虫的新疗法

基本信息

批准号：
10403664
负责人：
Dawn Marie Wetzel
金额：
$ 56.8万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403664
关键词：
ADME Study Affect Affinity African Trypanosomiasis Albendazole Ames Assay Amphotericin Anthelmintics Antiparasitic Agents Antiprotozoal Agents Binding Biological Biological Assay Biological Availability Biology Biomedical Research Cell division Chagas Disease Chemicals Clinical Collection Communicable Diseases Cutaneous Cutaneous Leishmaniasis Data Development Drug Kinetics Enhancers Evaluation Excretory function Frequencies Future Genetic Goals Human In Vitro Infection Institutes Ion Channel Kinetics Lead Leishmania Leishmaniasis Lesion Life Cycle Stages Malaria Mammalian Cell Medicine Metabolic Metabolism Microtubules Molecular Target Mus Mutation Oral Parasite resistance Parasites Parasitic Diseases Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Study Phenotype Plasma Property Proteins Publishing Rattus Research Resistance Resistance development Risk Safety Series Solubility Structure-Activity Relationship Testing Therapeutic Index Toxic effect Trypanosoma Trypanosoma brucei brucei Trypanosoma cruzi Trypanosomiasis Tubulin Validation Visceral Leishmaniasis Widespread Disease absorption alpha Tubulin analog aqueous benzimidazole beta Tubulin chemical property combat cytotoxic cytotoxicity extracellular high throughput screening human disease improved in vitro activity in vitro testing in vivo indexing inhibitor innovation lead candidate mouse model neglected tropical diseases novel novel therapeutics overexpression pathogen polymerization preclinical study prevent research and development resistance mechanism safety assessment scaffold screening side effect small molecule synergism targeted treatment

项目摘要

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.

项目摘要：发展中国家有 10 亿人面临利什曼病风险，每年有近 200 万人毁容或死亡。目前利什曼病及相关疾病的治疗方法寄生虫病人类非洲锥虫病和恰加斯病效果不佳且有毒。不可以治疗所有这三种传染病的药物是可用的。我们的长期目标是发展治疗锥虫感染的有效新药。通过筛选小分子化合物集合亚马逊利什曼原虫，我们发现了一种具有有效和选择性抗锥虫的新支架活动。我们最有效的类似物针对 L. amazonensis 无菌无鞭毛体的 EC50 为 15 nM（对于 L. amazonensis 无菌无鞭毛体，EC50 为 15 nM）细胞内无鞭毛体），选择性指数为 49。我们的化学系列具有广泛的功效范围，并且一些类似物的效力、选择性、溶解度和稳定性指标均超过已公布的先进标准。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虫药的作用。这些研究的目的是确定一种晚期先导化合物皮肤利什曼病治疗的潜力。在目标 1 中，我们将定义分子靶点我们的大院。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确定相关的结合伙伴。在目标 2 中，我们将通过体外鉴定抗利什曼尼化合物和体内功效。化合物将从经过验证的命中发展到早期先导化合物，然后如果满足的话，则发展到晚期先导化合物公布的标准。我们将使用迭代药物化学来提高功效和化学性质合成策略由级联告知的方法，其中包括体外效力测试针对寄生虫和微管蛋白，通过细胞毒性测定评估选择性，并表征 ADME 特性（例如代谢稳定性、水溶性和血浆稳定性）和药代动力学（PK）。到为了取得早期线索，化合物必须在概念验证小鼠模型中证明其功效皮肤利什曼病。为了进展到晚期线索，化合物必须治愈由一组引起的小鼠损伤皮肤利什曼原虫种类。我们最有前途的先导化合物将接受安全药理学研究（例如， CYP 抑制、Ames 测试和 CEREP 组）。我们还将确定潜在客户的产品概况未来发展和人类管理。在目标 3 中，我们将通过筛选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器针对亚马逊乳杆菌的活性。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和其他药物备份候选人以供进一步评估。我们的研究意义重大且具有创新性，因为它将增加目前有限的研发管线中具有新颖作用机制的化合物可以用来对抗这些被忽视的热带疾病。