Roberts Allison M, Ward Carl C, Nomura Daniel K
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, United States.
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, United States.
Curr Opin Biotechnol. 2017 Feb;43:25-33. doi: 10.1016/j.copbio.2016.08.003. Epub 2016 Aug 26.
Despite the completion of human genome sequencing efforts nearly 15 years ago that brought with it the promise of genome-based discoveries that would cure human diseases, most protein targets that control human diseases have remained largely untranslated, in-part because they represent difficult protein targets to drug. In addition, many of these protein targets lack screening assays or accessible binding pockets, making the development of small-molecule modulators very challenging. Here, we discuss modern methods for activity-based protein profiling-based chemoproteomic strategies to map 'ligandable' hotspots in proteomes using activity and reactivity-based chemical probes to allow for pharmacological interrogation of these previously difficult targets. We will showcase several recent examples of how these technologies have been used to develop highly selective small-molecule inhibitors against disease-related protein targets.
尽管近15年前就完成了人类基因组测序工作，带来了基于基因组的发现有望治愈人类疾病的前景，但大多数控制人类疾病的蛋白质靶点在很大程度上仍未转化为实际应用，部分原因是它们是难以成药的蛋白质靶点。此外，许多这些蛋白质靶点缺乏筛选检测方法或可及的结合口袋，这使得小分子调节剂的开发极具挑战性。在这里，我们讨论基于活性的蛋白质谱分析的现代化学蛋白质组学策略，以利用基于活性和反应性的化学探针在蛋白质组中绘制“可配体”热点，从而对这些以前难以攻克的靶点进行药理学研究。我们将展示几个最近的例子，说明这些技术是如何被用于开发针对疾病相关蛋白质靶点的高选择性小分子抑制剂的。
