Chemical characterization of SUMO specific proteases in Plasmodium falciparum

恶性疟原虫中 SUMO 特异性蛋白酶的化学表征

• 批准号: 8072189
• 负责人: Matthew Bogyo
• 金额: $ 19.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2012-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072189
• 关键词: Affect; Antimalarials; Biochemical; Biological; Biological Assay; Blood; Catalytic Domain; Cell Cycle; Cell Line; Cells; Cessation of life; Chemicals; Cysteine Proteinase Inhibitors; Data; Disease; Drug Delivery Systems; Enzymes; Eukaryota; Event; Excision; Exploratory/Developmental Grant; Fluorogenic Substrate; Funding; Gene Expression; Genetic Transcription; Goals; Hour; Human; Infection; Knowledge; Lead; Libraries; Life Cycle Stages; Light; Malaria; Mass Spectrum Analysis; Methods; Modification; Monitor; Nature; Parasites; Pathology; Pathway interactions; Pattern; Peptide Hydrolases; Phase; Plasmodium falciparum; Play; Population; Post-Translational Protein Processing; Process; Property; Protease Inhibitor; Proteins; Proteomics; Reagent; Regulation; Role; Staging; Substrate Specificity; Sumoylation Pathway; Technology; Therapeutic; Time; Transcriptional Regulation; Ubiquitin; Work; base; combinatorial; design; high risk; inhibitor/antagonist; insight; lead series; novel; novel therapeutics; obligate intracellular parasite; programs; protein protein interaction; public health relevance; scaffold; small molecule; tool; transcription factor

DESCRIPTION (provided by applicant): Malaria, a disease caused by the human protozoan parasite Plasmodium falciparum, affects 300-500 million people annually and is the cause of approximately 2 million deaths per year. The majority of disease pathology is associated with the 48 hour blood stage life cycle of the parasite. During this phase of infection, the parasite uses a highly regulated program of gene expression to orchestrate transition through several morphologically distinct phases. Currently, very little is known about the mechanisms used to achieve this high level of transcriptional control. Due to the absence of canonical eukaryotic transcription factors in P. falciparum, it is likely that post-translational modifications play important and unique roles in the regulation of the parasite life cycle. Small ubiquitin-related modifier (SUMO) is a protein that is used as a posttranslational modifier to alter the function of target proteins. SUMOylation is believed to regulate transcription, protein localization, protein- protein interactions, and the cell cycle. SUMO was recently identified in P. falciparum. Yet it remains difficult to dissect SUMOylation pathways because of the constant removal of SUMO from substrates and the essential nature of the SUMO-specific proteases (SENPs) that carry out this processing event. Thus, new tools that can be used to block the activity of the SENPs with a high degree of temporal control would be highly valuable for the study of SUMOylation in P. falciparum. This proposal outlines our plan to develop small molecule tools to perturb the function of the SENPs in P. falciparum. We hypothesize that SUMOylation is used as a critical regulatory mechanism by the parasite to control key processes necessary for survival inside the host. Therefore, inhibitors of these proteases will allow us to both validate SENPs as potential anti-malarial drug targets and also to isolate populations of SUMO modified proteins by proteomic methods. This data will provide information about how the parasite uses SUMOylation as a general regulatory mechanism. Ultimately, these reagents will help us to gain insight into the functional significance of SUMOylation and may lead to the identification of additional pathways that can be disrupted for therapeutic gain. PUBLIC HEALTH RELEVANCE: We hypothesize that SUMOylation is used as a critical regulatory mechanism by the obligate intracellular parasite Plasmodium falciparum to control key processes necessary for survival inside the host this project outlines plans to develop small molecule inhibitors of the proteases that regulate SUMO removal from substrate proteins. These compounds can be used to dissect the functional role of SUMOylation in the parasite life cycle. Ultimately this information may lead to new therapeutic strategies to treat malaria.

描述（由申请人提供）：疟疾是一种由人类原生动物寄生虫恶性疟原虫引起的疾病，每年影响3 -5亿人，每年造成约200万人死亡。大多数疾病病理与寄生虫的48小时血期生命周期有关。在这个感染阶段，寄生虫使用高度调控的基因表达程序来协调几个不同形态阶段的过渡。目前，关于实现这种高水平转录控制的机制知之甚少。由于恶性疟原虫缺乏典型的真核转录因子，翻译后修饰可能在寄生虫生命周期的调节中发挥重要而独特的作用。小泛素相关修饰物（Small ubiquitin-related modifier， SUMO）是一种用于改变靶蛋白功能的翻译后修饰物。SUMOylation被认为调节转录、蛋白定位、蛋白-蛋白相互作用和细胞周期。最近在恶性疟原虫中发现了SUMO。然而，由于从底物中不断去除SUMO以及执行这一加工事件的SUMO特异性蛋白酶（SENPs）的本质，解剖SUMO化途径仍然很困难。因此，可以用于阻断SENPs活性并具有高度时间控制的新工具对于恶性疟原虫sumo酰化的研究具有很高的价值。本提案概述了我们开发小分子工具来干扰恶性疟原虫SENPs功能的计划。我们假设SUMOylation是寄生虫控制宿主生存所需的关键过程的关键调控机制。因此，这些蛋白酶的抑制剂将使我们既可以验证SENPs作为潜在的抗疟疾药物靶点，也可以通过蛋白质组学方法分离SUMO修饰蛋白的群体。这些数据将提供关于寄生虫如何使用SUMOylation作为一般调节机制的信息。最终，这些试剂将帮助我们深入了解SUMOylation的功能意义，并可能导致鉴定其他可以被破坏以获得治疗效果的途径。