Biomolecular Recognition with Artificial Alpha Helices

描述（由申请人提供）：细胞功能取决于生物分子（蛋白质、RNA、DNA和碳水化合物）之间的高度特异性相互作用。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重要作用。可以预见地破坏这些相互作用的α-螺旋模拟物作为分子生物学的工具和药物开发的先导将是非常宝贵的。我们已经成功地创建了一个通用的方法来合成短的稳定的α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。交联的内部放置使得可以利用完整的螺旋功能进行分子识别。我们已经证明，这种新方法的结果异常稳定的人工α-螺旋。在这个应用程序中，我们探索这些人工螺旋的效用，针对复杂的信号网络。关于具体目标，（1）我们将创建一个构象和代谢稳健的HBS螺旋家族。(2)我们将建立一个实验确定的螺旋介导的蛋白质-蛋白质相互作用的结构数据库，并确定在螺旋蛋白质界面的热点残基。(3)我们将开发基于结构的配体，以帮助解码GT3信号网络，并评估发现蛋白激酶活性特异性抑制剂的新范例。结合这三个目标，将提供合理设计的蛋白质-蛋白质相互作用抑制剂，并验证我们的设计原则，植根于生物物理学和物理有机化学的基础理论。 公共卫生相关性：蛋白质-蛋白质相互作用的选择性调节是化学家和生物学家面临的巨大挑战。系统调节蛋白质-蛋白质相互作用的能力将极大地促进发现用于广泛疾病的候选治疗剂。该研究提供了一种合成方法，用于开发针对选定蛋白质界面的人工α-螺旋配体。

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.