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

基本信息

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
项目类别：
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

项目摘要

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 GTP 酶和进化相关的异三聚体 G 蛋白在 GDP 结合之间循环通常被认为是“关闭”的形式和直接参与下游的 GTP 结合形式控制这些蛋白质的不同细胞过程的效应子常常会破坏这一过程。核苷酸循环，特别是阻止结合的内在水解的突变 GTP 产生组成型活性 GTP 酶，导致多种人类疾病 - 大多数尽管组成型活性 GTP 酶在促进人类健康方面具有重要意义。疾病，很难使用传统的小分子来靶向这些蛋白质我们建议将几种正在开发的技术潜在地、选择性地整合到抑制剂中。这些技术包括使用定向的癌症中的组成型活性 GTP 酶。通过 mRNA 展示进行进化，以选择与活性物质具有高亲和力和特异性结合的肽 GTP酶；先进的合成化学将选定的肽转化为生物可利用的肽模拟物；以及几种新的靶向递送系统，包括纳米颗粒和配体-肽缀合物，将这些肽和肽模拟物递送至肿瘤以有效此外，这些肽还被用于实现新的功能。研究方向包括：i) 独特的高通量筛选，以重新评估潜力从传统的药物样库中鉴定活性 GTP 酶的小分子抑制剂，以及 ii) 创建生物传感器来监测高时空 GTP 酶的激活解决。