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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，通过以下途径入侵宿主细胞摄入未煮熟的受感染的肉或受污染的水。弓形虫感染了世界上30%的人口和目前美国自身的疾病成本估计为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，且有严重的副作用。因此，迫切需要新的药物和药物靶标。弓形虫的基因组是预测编码108个活性的激酶。激酶已被证明涉及方方面面弓形虫的生命周期，从宿主细胞的入侵到毒力。然而，缺乏商业上可用的可靠的激酶分析阻碍了弓形虫激动组导向的药物发现号。在这项应用中，我们的目标是开发和验证针对重要的激酶的分析与弓形虫寄生虫的生活史有关，后者负责传播和疾病病理。这些基于我们的三杂交分离荧光素酶系统的弓形虫激酶特异性检测将是进一步用于高通量筛选激酶靶向抑制物库。这些努力是具有重大意义和创新性，因为识别靶向特定的抑制剂不仅将提供用于进一步药物开发的药效团，但也确定用于研究的化学探针为激酶生物学和信号通路提供新的干预手段。