Targeting a New Therapy for Trypanosomatids

针对锥虫的新疗法

基本信息

批准号：
10642869
负责人：
Dawn Marie Wetzel
金额：
$ 58.42万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642869
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 Endowment Enhancers Evaluation Excretory function Frequencies Future Genetic Goals Human In Vitro Infection 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 Polymers Property Protozoa Publishing Rattus Recommendation 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 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 meter mouse model neglected tropical diseases novel novel therapeutics overexpression pathogen polymerization preclinical study prevent protein purification research and development 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：发展中国家十亿人面临着利什曼病的风险，每年毁容或杀死近200万人。利什曼病和相关的当前疗法寄生疾病患有非洲人类锥虫病，chagas病有效和有毒。不可以治疗所有这三种传染病的药物可用。我们的长期目标是发展有效的锥形剂感染新药。通过筛选针对的小分子化合物收集利什曼尼亚亚马逊人，我们已经确定了一个新的脚手架，并具有有效和选择性的反tryosomatid 活动。我们最有效的类似物的EC50为15 nm，针对亚马逊乳杆菌的Amazonis axenic amastigotes（50 nm 细胞内膜片）和49的选择性指数。我们的化学系列具有广泛的功效范围，并且几个类似物具有对已发表的进步标准的效力，选择性，溶解度和稳定指数。我们的数据表明，这些化合物有助于微管蛋白聚合，这将是一种新的机制抗营养药物的作用。这些研究的目的是确定与有可能进步治疗皮肤利什曼病。在AIM 1中，我们将定义分子靶我们的化合物。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确定相关的约束伙伴。在AIM 2中，我们将在体外鉴定出抗精神病药物化合物和体内功效。化合物将从验证的命中率转变为早期的铅，然后在较晚的铅中，如果他们见面已发布标准。我们将使用迭代药物化学提高功效和化学特性级联的综合策略在其中包括测试体外效力的方法针对寄生虫和微管蛋白，用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）。到进展到早期铅，化合物必须在概念验证鼠标模型中证明功效皮肤利什曼病。为了发展到较晚的铅，化合物必须治愈由面板引起的小鼠病变皮肤利什曼原虫物种。我们最有希望的潜在客户将接受安全药理学研究（例如， CYP抑制作用，AMES测试和小脑面板）。我们还将确定潜在客户的产品概况未来的发展和人类行政管理。在AIM 3中，我们将通过筛选来获得备用脚手影响小管蛋白动力学的抗抗菌药物。我们将确定寄生虫的选择性哺乳动物微管蛋白并测试针对亚马逊乳杆菌活性的最有效和选择性小管蛋白效应子。目标完成后，我们将确定皮肤利什曼病和其他的较晚铅化合物备份候选人进行进一步评估。我们的研究具有重要和创新性，因为它会增加具有新颖的作用机理的化合物，目前是有限的研发管道可用于打击这些被忽视的热带疾病。