Inhibition of GTPases and G proteins to treat human disease

抑制 GTP 酶和 G 蛋白来治疗人类疾病

• 批准号: 9750731
• 负责人: Rihe Liu
• 金额: $ 35.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750731
• 关键词: Affinity; Avidity; Binding; Bioavailable; Biosensor; Cancer cell line; Cardiovascular system; Cell Proliferation; Cell physiology; Cells; Cellular biology; Clinical; Crystallography; Cytosol; Data; Development; Directed Molecular Evolution; Disease; Experimental Designs; Family; Family Study; Future; G-Protein-Coupled Receptors; G-substrate; GTP Binding; GTP-Binding Proteins; Generations; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; Hearing; Hemostatic function; Heterotrimeric GTP-Binding Proteins; Hormonal; Human; Hydrolysis; Immune; Isoenzymes; KRAS2 gene; Lead; Libraries; Ligands; Lipids; Malignant Neoplasms; Messenger RNA; Metabolic; Molecular; Monitor; Monomeric GTP-Binding Proteins; Mutate; Mutation; Nucleotides; Oncogenes; Peptides; Pharmaceutical Preparations; Phosphotransferases; Production; Property; Proteins; Purine Nucleotides; Reagent; Regulation; Research; Resolution; Signal Transduction; Specificity; Surface; Synthesis Chemistry; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Uveal Melanoma; Vision; base; calcium phosphate; design; developmental disease; high throughput screening; human disease; in vivo; inhibitor/antagonist; member; mouse model; nanomolar; nanoparticle; nervous system disorder; novel; novel strategies; peptidomimetics; prevent; self assembly; small molecule inhibitor; small molecule therapeutics; spatiotemporal; success; targeted delivery; targeted treatment; tumor; tumorigenesis; uptake

PROJECT ABSTRACT Small GTPases and evolutionarily-related heterotrimeric G proteins cycle between GDP-bound forms that are typically considered “off” and GTP-bound forms that directly engage downstream effectors to control diverse cellular processes. Mutations in these proteins often disrupt this nucleotide cycling, and in particular, mutations that prevent the intrinsic hydrolysis of bound GTP lead to constitutively active GTPases that contribute to a variety of human diseases - most notably cancer. Despite the significance of constitutively active GTPases in promoting human diseases, it has been difficult to target these proteins using conventional small molecule inhibitors. We propose to integrate several developing technologies to potently and selectively target constitutively active GTPases in cancers. These technologies include the use of directed evolution by mRNA display to select peptides that bind with high affinity and specificity to active GTPases; advanced synthetic chemistries to convert selected peptides into bioavailable peptidomimetics; and several new targeted delivery systems, including nanoparticles and ligand-peptide conjugates, to deliver these peptides and peptidomimetics to tumors for efficient dispersal and GTPase inhibition. In addition, these peptides are being used to enable new research directions including: i) unique high-throughput screens to reassess the potential to identify small molecule inhibitors of active GTPases from conventional, drug-like libraries and ii) the creation of biosensors to monitor the activation of GTPases with high spatiotemporal resolution.

项目摘要 小的GTPases和与GDP结合之间的与进化相关的异三聚体G蛋白周期 通常被认为是“关闭”和GTP结合形式的形式，直接参与下游 控制科学细胞过程的影响。这些蛋白质中的突变经常破坏这一点 核苷酸循环，尤其是防止结合的内在水解的突变 GTP导致组成性活跃的GTP酶，导致各种人类疾病 - 大多数 值得注意的癌症。尽管组成性活跃的GTPases在促进人类方面具有重要意义 疾病，很难使用常规的小分子靶向这些蛋白质 抑制剂。我们建议将几种发展的技术整合到潜在和有选择的 癌症中的组成性活性GTPase。这些技术包括使用指导 mRNA显示的进化以选择具有高亲和力结合和特异性的肽 GTPases；先进的合成化学化学，将选定的辣椒转换为生物利用 辣妹；以及几个新的目标交付系统，包括纳米颗粒和 配体肽缀合物，将这些宠物和胡椒纤维纤维固定在肿瘤中以有效 分散和GTPase抑制。此外，这些宠物被用来启用新的 研究说明包括：i）独特的高通量屏幕，以重新评估潜力 从常规，类似药物的文库和II中鉴定活性GTPase的小分子抑制剂） 生物传感器的创建以监测具有高时空的GTPase的激活 解决。