Biomolecular Recognition with Artificial Alpha Helices

描述（由申请人提供）：细胞功能依赖于生物分子（蛋白质、RNA、DNA和碳水化合物）之间高度特异性的相互作用。α -螺旋是蛋白质结构中无处不在的元素，在许多这些相互作用中起着重要作用。α -螺旋模拟物可以预见地破坏这些相互作用，作为分子生物学的工具和药物开发的先导，它将是无价的。我们已经成功地创造了一种合成短稳定α螺旋的通用方法，可以靶向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。交联的内部位置使得利用完整的螺旋功能进行分子识别成为可能。我们已经证明了这种新方法可以产生异常稳定的人工α螺旋。在这个应用中，我们探讨了这些人造螺旋在复杂信号网络中的应用。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)构建螺旋蛋白介导蛋白相互作用的实验确定结构数据库，确定螺旋蛋白界面中的热点残基。(3)我们将开发基于结构的配体来帮助解码GTPase信号网络，并评估发现特定蛋白激酶活性抑制剂的新范例。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，并验证我们基于生物物理学和物理有机化学基础理论的设计原则。

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.