Enabling Malarial Kinome Directed Drug Discovery

实现疟疾激酶组定向药物发现

• 批准号: 8714538
• 负责人: REENA ZUTSHI
• 金额: $ 22.43万
• 依托单位: LUCEOME BIOTECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714538
• 关键词: African Trypanosomiasis; Antimalarials; Area; Artemisinins; Binding; Biological Assay; Biology; Bioluminescence; Bite; Cessation of life; Chemicals; Chloroquine; Communicable Diseases; Culicidae; Data; Development; Disease; Drug Combinations; Drug Targeting; Drug resistance; Erythrocytes; FDA approved; Folic Acid Antagonists; Functional disorder; Genome; Goals; Growth; Human; Hybrids; Investments; Leishmania major; Leishmaniasis; Letters; Libraries; Life Cycle Stages; Light; Luciferases; Malaria; Methods; Parasites; Pathology; Pharmaceutical Preparations; Phase; Phosphotransferases; Plasmodium; Plasmodium falciparum; Private Sector; Production; Public Sector; Reporting; Research; Resistance; Scaffolding Protein; Signal Pathway; Staging; System; Technology; Time; Toxoplasma gondii; Toxoplasmosis; Trypanosoma brucei brucei; Vaccines; Validation; Virulent; World Health Organization; artemisinine; asexual; base; cDNA Library; chemotherapy; combat; cost; drug development; drug discovery; effective therapy; high throughput screening; human disease; inhibitor/antagonist; innovation; kinase inhibitor; mortality; mutant; pharmacophore; public health relevance; standard of care

DESCRIPTION (provided by applicant): World Health Organization (WHO) estimates that there are 154-289 million cases of malaria and 610,000-971,000 deaths each year. Malaria is caused by a protozoan parasite, Plasmodium, which is transmitted through the bite of a mosquito. In the absence of an effective vaccine against Malaria, chemotherapy remains the only viable treatment option. However with emerging reports of acquired resistance against antifolates and chloroquine, and more recently artemisinin, there is an urgent need for new drugs and drug targets. The genome of Plasmodium falciparum, the species responsible for most mortality, has been sequenced and is predicted to encode 86-99 kinases. Recent high throughput screening efforts of large compound libraries have identified numerous potent hits, which have chemotypes reminiscent of kinase inhibitors. However, the lack of commercially available robust kinase assays has hindered Plasmodium kinome-directed drug discovery. In this application, we aim to develop assays targeted against the kinases expressed in the asexual stage of the parasite's life-cycle, which is responsible for the pathology associated with the disease. Recent studies have identified 36 kinases expressed in this stage that are critical to the parasite's survival, which will serve as our initial targets. These Plasmodium kinase specific assays, based on a three-hybrid split luciferase system, will be further used for high throughput screening of anti-malarial compound libraries. These efforts are both significant and innovative as the identification of target specific inhibitors will not only provide pharmacophores for furthe drug development but also identify chemical probes for studying kinase biology and signaling pathways.

描述(申请人提供)：世界卫生组织(WHO)估计，每年有1.54亿-2.89亿疟疾病例和610,000-971,000人死亡。疟疾是由原生动物寄生虫疟原虫引起的，这种寄生虫通过蚊子的叮咬传播。在缺乏有效的疟疾疫苗的情况下，化疗仍然是唯一可行的治疗选择。然而，随着对抗叶酸和氯喹以及最近的青蒿素产生获得性耐药性的报道不断出现，迫切需要新的药物和药物靶点。恶性疟原虫是导致大多数死亡的物种，其基因组已经被测序，预计编码86-99个激酶。最近对大型化合物文库的高通量筛选工作已经确定了许多有效的命中，它们的化学类型使人想起激酶抑制剂。然而，缺乏商业上可用的可靠的激酶分析阻碍了疟原虫以激动组为导向的药物发现。在这项应用中，我们的目标是开发针对寄生虫生命周期无性阶段表达的激酶的分析，这是与疾病相关的病理学的责任。最近的研究已经确定了在这一阶段表达的36个激酶，它们对 寄生虫的生存，这将是我们最初的目标。这些基于三杂交裂解荧光素酶系统的疟原虫激酶特异性分析将进一步用于高通量筛选抗疟疾化合物文库。这些努力具有重大意义和创新性，因为识别靶向特异性抑制剂不仅将为Furthe药物开发提供药效团，还将识别用于研究激酶生物学和信号通路的化学探针。