Inhibition of GTPases and G proteins to treat human disease

项目摘要 GDP结合的小GTP酶和进化相关的异源三聚体G蛋白周期 通常被认为是“关闭”的表单和直接与下游接合的GTP绑定表单 控制不同细胞过程的效应器。这些蛋白质的突变通常会破坏这一点 核苷酸循环，特别是阻止结合的内在水解性突变 GTP导致结构性活跃的GTP酶，导致多种人类疾病-大多数 尤其是癌症。尽管结构性活性GTP酶在促进人类 疾病，已经很难用传统的小分子靶向这些蛋白质 抑制剂。我们建议集成几种正在开发的技术，以有效和选择性地 靶向癌症中具有结构性活性的GTP酶。这些技术包括使用定向的 通过mRNA显示进化以选择与活性具有高亲和力和特异性的肽 GTP酶；将选定的多肽转化为生物可利用的先进合成化学 以及几种新的靶向递送系统，包括纳米粒和 配体-多肽结合物，将这些多肽和多肽仿制物有效地输送到肿瘤中 分散和GTP酶抑制。此外，这些多肽正被用来使新的 研究方向包括：i)独特的高通量筛选，以重新评估 从传统的类药物文库中鉴定活性GTP酶的小分子抑制剂和ii) 用于监测GTP酶高时空活性的生物传感器的建立 决议。

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.