Molecular Cloaking Devices for Manipulation of Cysteine Post-Translational Modifications

项目摘要 蛋白质的翻译后修饰(PTM)几乎参与了所有的细胞信号通路。 对这些事件的药物干预是药物开发的重要策略。在这个项目中，我们 建议建立一个发现半胱氨酸翻译后共价抑制剂的新平台 修饰，特别是H-RAS和K-RAS的C-末端的戊烯基化。这些事件对于 这些蛋白质的致癌突变以驱动细胞不受控制的生长和分裂。与典型的 阻断PTMS的策略，我们将筛选与修饰的大环共价结合的非肽大环 底物蛋白(H-RAS或K-RAS)上的表位，而不是以修饰酶为靶点的化合物。在……里面 这样，我们相信将有可能以前所未有的选择性操纵单个PTM。

Project Summary Post-translational modifications (PTMs) of proteins are involved in virtually all cellular signaling pathways. Pharmacological intervention in these events is an important strategy for drug development. In this project, we propose to establish a novel platform for the discovery of covalent inhibitors of cysteine post-translational modifications, in particular, the prenylation of the C-termini of H-Ras and K-Ras. These events are critical for oncogenic mutants of these proteins to drive cell uncontrolled growth and division. In contrast to typical strategies for blocking PTMs, we will screen for non-peptidic macrocycles that bind covalently to the modified epitope on the substrate protein (H-Ras or K-Ras), rather than compounds that target the modifying enzyme. In this way, we believe it will be possible to manipulate single PTMs with unprecedented selectivity.