Biomolecular Recognition with Artificial Alpha Helices

描述(申请人提供)：细胞功能依赖于生物分子(蛋白质、RNA、DNA和碳水化合物)之间高度特异的相互作用。α-螺旋是蛋白质结构中普遍存在的元素，在许多这些相互作用中发挥着基础作用。可以预测地破坏这些相互作用的α-螺旋模拟作为分子生物学的工具和药物开发的先导将是非常有价值的。我们已经成功地创建了一种合成短的稳定的阿尔法螺旋的通用方法，这种螺旋可以针对选定的生物分子相互作用。我们的策略包括用共价键取代目标α-螺旋中的一个主链氢键。交联剂的内部放置使其能够利用完整的螺旋功能进行分子识别。我们已经证明，这种新方法产生了异常稳定的人工α-螺旋。在这个应用中，我们探索了这些人造螺旋的用途，以定位复杂的信令网络。关于具体目标，(1)我们将创建一个构象和代谢强大的HBS螺旋家族。(2)我们将构建一个实验确定的螺旋介导的蛋白质-蛋白质相互作用结构的数据库，并确定螺旋蛋白质界面上的热点残基。(3)我们将开发基于结构的配体来帮助破译GTPase信号网络，并评估发现蛋白激酶活性特异性抑制剂的新范式。将这三个目标结合起来将提供合理设计的蛋白质-蛋白质相互作用抑制剂，并验证我们植根于生物物理学和物理有机化学基本理论的设计原则。 公共卫生相关性：选择性地调节蛋白质-蛋白质相互作用对化学家和生物学家来说是一个巨大的挑战。系统地调节蛋白质-蛋白质相互作用的能力将极大地促进对广泛疾病的候选治疗剂的发现。这项研究提供了一种合成方法来开发人工α-螺旋配体，用于靶向选定的蛋白质界面。

DESCRIPTION (provided by applicant): Cellular function depends on highly specific interactions between biomolecules (proteins, RNA, DNA, and carbohydrates). Alpha-helices, ubiquitous elements of protein structures, play fundamental roles in many of these interactions. Alpha-helix mimetics that can predictably disrupt these interactions would be invaluable as tools in molecular biology, and as leads in drug development. We have succeeded in creating a general approach for the synthesis of short stable alpha helices that can target chosen biomolecular interactions. Our strategy involves replacement of one of the main chain hydrogen bonds in the target alpha-helix with a covalent bond. The internal placement of the crosslink makes it possible to take advantage of the full helix functionality for molecular recognition. We have demonstrated that this new method results in unusually stable artificial alpha-helices. In this application, we explore the utility of these artificial helices for targeting complex signaling networks. With regards to specific aims, (1) We will create a conformationally and metabolically robust family of HBS helices. (2) We will construct a database of experimentally determined structures of helix-mediated protein-protein interactions and determine hot-spot residues in the helical protein interfaces. (3) We will develop structure-based ligands to help decode the GTPase signaling networks, and evaluate a new paradigm for discovery of specific inhibitors of protein kinase activity. Combined these three aims will offer rationally designed inhibitors of protein- protein interactions, and validate our design principles that are rooted in the fundamental theories of biophysics and physical organic chemistry. PUBLIC HEALTH RELEVANCE: Selective modulation of protein-protein interactions is a grand challenge for chemists and biologists. The ability to systematically modulate protein-protein interactions would greatly facilitate the discovery of candidate therapeutic agents for a broad range of diseases. The proposed research offers a synthetic method for developing artificial alpha-helical ligands for targeting chosen protein interfaces.