Protein Recognition by Peptidic Foldamers

描述（由申请人提供）：折叠物是一种非自然的低聚物，具有离散和可预测的折叠行为。提出的研究探索折叠体模仿天然蛋白质的识别表面的能力，从而阻止特定蛋白质-蛋白质复合物的形成。特定蛋白质对之间的相互作用对生命系统的调节和信息传递至关重要。病理相互作用导致许多人类疾病。这种相互作用通常很难用小分子（传统上首选的药物来源）来抑制，因为当一个大分子与另一个大分子结合时，大的表面积被掩盖了。我们工作背后的一个主要假设是，文件夹可以为合理开发蛋白质-蛋白质相互作用抑制剂提供基础。我们在三个系统中测试这个假设。首先，我们试图模拟α -螺旋Bcl-2同源-3 （BH3）结构域，这是天然促凋亡蛋白的片段，可被抗凋亡伴侣蛋白上的互补裂缝识别。该系统为我们的工作提供了一个很好的测试平台，因为可以进行稳健的基于蛋白质的分析，并且具有获得热力学数据和高分辨率结构数据的良好前景。BH3结构域模仿的成功策略将在更长的α -螺旋靶点，即HIV蛋白gp41的c端七肽重复（CHR）片段的背景下进行研究。为了使病毒感染靶细胞，CHR螺旋必须停靠在gp41的另一部分形成的互补裂缝中。阻断这种相互作用可以阻断感染。我们假设的最后测试集中在抑制血管内皮生长因子（VEGF）之间的相互作用，VEGF是一种可溶性信号蛋白及其细胞表面受体。VEGF诱导新血管的发育（“血管生成”），而VEGF诱导的异常血管生成与许多人类疾病有关。在我们研究的这一部分中确定的策略最终可以使我们开发出折叠蛋白拮抗剂，用于细胞表面发生的广泛的蛋白质-受体相互作用。公共卫生相关性：特定蛋白质之间的相互作用对正常的人体生理至关重要，而异常的相互作用是许多疾病的基础。我们研究的主要目标是探索阻断异常蛋白-蛋白相互作用的新策略。我们的实验是非常基础的，但结果可能为新的治疗策略提供基础。我们试图干扰蛋白质之间相互作用的试剂是折叠成明确形状的低聚物（“折叠体”）。

DESCRIPTION (provided by applicant): Foldamers are unnatural oligomers that display discrete and predictable folding behavior. The proposed research explores the ability of foldamers to mimic recognition surfaces on natural proteins and thereby block the formation of specific protein-protein complexes. Interactions between specific pairs of proteins are critical for regulation and information transfer in living systems. Pathological interactions contribute to many human diseases. Such interactions are often difficult to inhibit with small molecules (the traditionally preferred source for drugs) because large surface areas are buried when one macromolecule binds to another. A principal hypothesis behind our work is that foldamers could provide a basis for rational development of inhibitors of protein-protein interactions. We are testing this hypothesis in three systems. First, we are trying to mimic alpha-helical Bcl-2 homology-3 (BH3) domains, segments of natural pro-apoptotic proteins that are recognized by complementary clefts on anti-apoptotic partner proteins. This system represents an excellent testbed for our efforts because robust protein-based assays are available, and there is a good prospect of acquiring thermodynamic data and high-resolution structural data. Strategies that are successful for BH3 domain mimicry will be examined in the context of a longer alpha-helical target, the C-terminal heptad repeat (CHR) segment of the HIV protein gp41. The CHR helix must dock into a complementary cleft formed by another portion of gp41 in order for the virus to infect target cells. Blocking this interaction can block infection. The final test of our hypothesis focuses on inhibiting interactions between vascular endothelial growth factor (VEGF), a soluble signaling protein and its cell-surface receptors. VEGF induces development of new blood vessels ("angiogenesis"), and aberrant VEGF-induced angiogenesis is associated with a number of human diseases. Strategies identified in this component of our research could ultimately enable us to develop foldamer antagonists for a wide range of protein-receptor interactions that occur at the cell surface. PUBLIC HEALTH RELEVANCE: Interactions between specific proteins are critical for normal human physiology, and aberrant interactions underlie many diseases. The major goal of our research is to explore new strategies for blocking aberrant protein-protein interactions. Our experiments are very basic, but the results might provide a foundation for new therapeutic strategies. The agents with which we try to interfere with protein-protein interactions are oligomers that fold into well-defined shapes ("foldamers").