School of Biomedical Sciences, University of Nottingham, Nottingham, UK.
Nat Rev Drug Discov. 2011 Jan;10(1):29-46. doi: 10.1038/nrd3321. Epub 2010 Dec 10.
The ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.
泛素-蛋白酶体系统 (UPS) 和泛素样蛋白 (UBL) 缀合途径是细胞蛋白质动态平衡的重要组成部分。人们越来越认识到这些途径对正常细胞功能和疾病的重要性，这促使人们深入寻找选择性阻断这些途径功能的小分子抑制剂。然而，我们对 UBL 缀合的分子机制和生物学后果的认识有限，这是识别这些途径中酶靶标的类药抑制剂的一个重大障碍。在这里，我们重点介绍了对这些酶的一些作用的最新认识，以及这些新的见解如何成为为包括免疫炎症性疾病、癌症、传染病、心血管疾病和神经退行性疾病在内的疾病开发新型治疗方法的关键。
