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Identification of preclinical drug candidates for the treatment of schistosomiasis

治疗血吸虫病的临床前候选药物的鉴定

基本信息

批准号：
9813829
负责人：
Pavel A Petukhov
金额：
$ 49.07万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813829
关键词：
Adolescent Animal Model Antioxidants Binding Binding Sites Biochemical Biochemistry Biological Assay Biological Availability Cell Survival Cells Cessation of life Chemicals Chronic Disease Clinical Collaborations Complement Complex Computer Assisted Computer-Aided Design Country Crystallization Development Diagnostic Disease Drug Targeting Drug resistance Enzymes Evolution Funding Glutathione Reductase Human In Vitro Infection International Interruption Libraries Ligands Liver Microsomes Mammalian Cell Mediator of activation protein Medical Metabolic Molecular Molecular Target Morbidity - disease rate Mus Oral Oxadiazoles Oxidation-Reduction Oxides Parasite resistance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Plasma Praziquantel Praziquantel resistance Prevalence Property RNA Interference Recombinant Proteins Research Resistance Schistosoma Schistosome Parasite Schistosomiasis Selenocysteine Seminal Structure Study models TXN gene Toxic effect United States National Institutes of Health Vertebrates X-Ray Crystallography analog base candidate selection chemoproteomics chemotherapy cytotoxicity design disability drug candidate drug development drug discovery enzyme activity glutaredoxin high throughput screening improved in vivo inhibitor/antagonist innovation iterative design lead optimization mouse model neglect new therapeutic target next generation novel novel therapeutics pharmacokinetics and pharmacodynamics pre-clinical small molecule small molecule inhibitor structural biology thioredoxin reductase transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT Schistosome parasites infect 200 million people, resulting in significant morbidity and more than 200,000 deaths annually. Schistosomiasis control strategies rely almost exclusively on chemotherapy and tens of millions of people are treated with the only available drug, praziquantel (PZQ). There are no new drugs in the clinical pipeline. PZQ cure rates obtained in mass drug administration campaigns are typically less than 50%. Furthermore, with projected levels of PZQ use it is inevitable that PZQ-resistant parasites will evolve. Therefore, it is imperative to identify new drug targets and drugs for schistosomiasis treatment. We identified a highly promising drug target: the worm selenocysteine-containing enzyme thioredoxin glutathione reductase (TGR). We established that TGR is a central and essential mediator of antioxidant defenses in the worm. The antioxidant defenses of vertebrates are diversified to three independent enzymes, glutathione reductase, thioredoxin reductase, and glutaredoxin, whereas schistosomes rely solely on TGR. TGR is a chokepoint and its inhibition leads to rapid worm death in all developmental stages. In contrast, PZQ has poor activity against juvenile worms, often resulting in partial cures. We have shown that TGR is druggable, can be selectively targeted over human orthologous enzymes and that its inhibition in worms in an animal model of schistosomiasis leads to worm death. PZQ analogs are inactive, restricting analog development to avoid or counteract drug resistance. Unlike PZQ for which the mechanism of action is not known, TGR is a defined molecular target, active as a recombinant protein, with established biochemical assays amenable to rapid compound analysis, SAR, and optimization. We recently completed a multi-tiered HTS of a large compound library (>350,000 compounds), which identified >100 TGR inhibitors that were inactive against off-target, orthologous human enzymes and nontoxic to mammalian cells. The identification of these hits demonstrates that specific inhibitors of TGR can be obtained without off-target interactions and cytotoxicity. We have obtained both liganded and ligand-free crystal structures of TGR, allowing a structure based approach to hit optimization. We hypothesize that iterative medicinal chemistry optimization will yield potent and selective small molecule TGR inhibitors that will have in vivo worm killing activity. In the R21 phase our aims are to identify hits from the multi-tiered HTS with potent (< 5 µM) worm killing activity and to characterize the TGR binding site of these inhibitors by co-crystallization with TGR and crystal structure determination. In the R33 phase we propose to optimize these novel, potent TGR inhibitors using cutting-edge, structure and ligand- based computer-aided design and medicinal chemistry to improve potency, stability, and oral bioavailability. This will be complemented by X-ray crystallography and chemoproteomics using photoreactive probes to characterize molecular TGR-compound interactions. Medicinal chemistry will be informed by enzymatic analysis of TGR and orthologous human enzymes, metabolic stability, in vitro cell toxicity, and activity against ex vivo worms. Finally, select compounds will be assessed for PK/PD properties and efficacy against schistosome infections in mice. To accomplish these transformative aims, an innovative international collaboration of global experts with expertise in schistosome biochemistry and drug discovery, structural biology, computer-aided molecular design, and chemoproteomics has been assembled. The varied and synergistic expertise of the team will facilitate overcoming critical barriers to drug development. Completion of the project will identify preclinical drug-like compounds, suitable for candidate selection for schistosomiasis treatment.

项目总结/文摘