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Enabling Toxoplasma gondii Kinome Directed Drug Discovery

实现弓形虫激酶组定向药物发现

基本信息

批准号：
10602259
负责人：
REENA ZUTSHI
金额：
$ 100万
依托单位：
LUCEOME BIOTECHNOLOGIES, LLC
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：
2019-03-11 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602259
关键词：
Acceleration Antimalarials Biological Assay Biology Bioluminescence Biotechnology Cells Chemicals Communities Cost of Illness Data Development Dimerization Disease Drug Targeting Encephalitis Eye diseases Genome Goals Growth Human Hybrids Immunocompetent Immunocompromised Host In Vitro Individual Infection Ingestion Intervention Invaded Letters Libraries Life Cycle Stages Light Luciferases Malaria Meat Parasites Pathology Phase Phosphotransferases Plasmodium falciparum Population Pregnant Women Production Publications Pyrimethamine Reporting Research Scaffolding Protein Signal Pathway Sulfadiazine System Technology Toxoplasma Toxoplasma gondii Toxoplasmosis Treatment Protocols United States Vertical Disease Transmission Virulence acute infection asexual assay development cell motility chemical binding chemical conjugate chronic infection contaminated water cost design drug development drug discovery effective therapy high throughput screening human disease in vivo inhibitor innovation kinase inhibitor luminescence novel therapeutics pharmacophore prevent research and development screening side effect success transmission process uncooked

项目摘要

Project Summary Toxoplasma gondii (T.gondii), the causative agent for toxoplasmosis, invades host cells through ingestion of uncooked infected meat or contaminated water. T.gondii infects 30% of the world’s population and the current cost of the disease in US itself is estimated to be $3B and rising. Current treatment regimen is effective only against acute infection and has severe side effects. Hence there is an urgent need for new drugs and drug targets. The genome of T.gondii, is predicted to encode 108 active kinases. Kinases have been shown to be involved in every aspect of the life cycle of T.gondii, from invasion of host cells to virulence. However, the lack of commercially available robust kinase assays has hindered T.gondii kinome-directed drug discovery. In this application, we aim to develop and validate assays targeted against the kinases essential to the T.gondii parasite’s life-cycle, which is responsible for transmission and disease pathology. These T.gondii kinase specific assays, based on our three-hybrid split luciferase system, will be further used for high throughput screening of a kinase targeted inhibitor library. These efforts are both significant and innovative as the identification of target specific inhibitors will not only provide pharmacophores for further drug development but also identify chemical probes for studying kinase biology and signaling pathways to provide new interventions.

项目摘要弓形虫是弓形虫病的病原体，通过感染宿主细胞，进食未经烹煮的受感染肉类或受污染的水。弓形虫感染了世界上30%的据估计，美国目前的疾病成本为30亿美元，而且还在上升。目前的治疗方案仅对急性感染有效，并且具有严重的副作用。因此，迫切需要新的药物和药物靶点。弓形虫的基因组是预计编码108种活性激酶。激酶已被证明参与了各个方面弓形虫的生命周期，从入侵宿主细胞到毒力。但缺乏商业上可获得的强大的激酶测定阻碍了弓形虫激酶组定向药物的发现在这项应用中，我们的目标是开发和验证针对关键激酶的检测方法。弓形虫寄生虫的生命周期，负责传播和疾病病理学。这些弓形虫激酶特异性检测，基于我们的三杂交分裂荧光素酶系统，将是进一步用于激酶靶向抑制剂文库的高通量筛选。这些努力这是重要的和创新的，因为靶特异性抑制剂的鉴定不仅提供了药效团用于进一步的药物开发，还可以识别化学探针用于研究激酶生物学和信号通路，以提供新的干预措施。