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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10亿人面临感染利什曼病的风险