Inhibition of GTPases and G proteins to treat human disease

项目摘要 小GTP酶和进化相关的异源三聚体G蛋白在GDP结合的 通常被认为是“关闭”的形式和直接与下游结合的GTP结合形式 控制不同细胞过程的效应器。这些蛋白质中的突变通常会破坏这一点。 核苷酸循环，特别是阻止结合的核苷酸的内在水解的突变， GTP导致组成型活性GTP酶，其导致多种人类疾病-大多数 尤其是癌症。尽管组成型活性GTP酶在促进人类免疫应答中具有重要意义， 疾病，很难使用常规的小分子靶向这些蛋白质， 抑制剂的我们建议将几种发展中的技术结合起来， 靶向癌症中的组成型活性GTP酶。这些技术包括使用定向 通过mRNA展示进化来选择以高亲和力和特异性结合活性肽的肽， GTP酶;将选定肽转化为生物可利用肽的高级合成化学 肽模拟物;和几种新的靶向递送系统，包括纳米颗粒和 配体-肽缀合物，以将这些肽和肽模拟物递送至肿瘤， 分散和GT3抑制。此外，这些肽被用来使新的 研究方向包括：i）独特的高通量筛选，以重新评估 从常规药物样文库中鉴定活性GTP酶的小分子抑制剂，和ii） 生物传感器的创建，以监测具有高时空的GTP酶的激活， 分辨率

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.