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.

项目摘要弓形虫弓形虫（T.Gondii），弓形虫病的病因，通过摄取未煮过的被感染的肉或污染的水。 T.Gondii感染了世界的30％据估计，我们本身的疾病本身的人口和目前的疾病成本为$ 3B，而且上涨。当前的治疗方案仅有效防止急性感染，并且具有严重的副作用。因此，迫切需要新药和药物靶标。 t.gondii的基因组是预测编码108个活性激酶。激酶已被证明与各个方面有关 T.gondii的生命周期，从侵袭宿主细胞到病毒。但是，缺乏市售的强大激酶分析阻碍了T.Gondii Kinome指导的药物发现。在此应用中，我们旨在开发和验证针对激酶必不可少的针对激酶致力于传播和疾病病理学的T.Gondii寄生虫的生命周期。这些T.Gondii激酶特定的分析，基于我们的三杂交分裂荧光素酶系统，将是进一步用于对靶向抑制剂库的高吞吐量筛选。这些努力是重要的和创新的，因为识别目标特定抑制剂不仅会提供用于进一步药物开发的药物团，但也确定了研究的化学问题激酶生物学和信号通路提供新的干预措施。