Bano Iqra, Malhi Moolchand, Zhao Min, Giurgiulescu Liviu, Sajjad Hira, Kieliszek Marek
Department of Veterinary Physiology and Biochemistry, Shaheed Benazir Bhutto University of Veterinary and Animals Sciences Sakrand (SBBUVAS), Sakrand, 67210 Sindh Pakistan.
Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University, Tandojam, Pakistan.
3 Biotech. 2022 Apr;12(4):103. doi: 10.1007/s13205-022-03162-x. Epub 2022 Mar 29.
The cullin-RING E3 ligases (CRLs) are the biggest components of the E3 ubiquitin ligase protein family, and they represent an essential role in various diseases that occur because of abnormal activation, particularly in tumors development. Regulation of CRLs needs neddylation, a post-translational modification involving an enzymatic cascade that transfers small, ubiquitin-like NEDD8 protein to CRLs. Many previous studies have confirmed neddylation as an enticing target for anticancer drug discoveries, and few recent studies have also found a significant increase in advancement in protein neddylation, including preclinical and clinical target validation to discover the neddylation inhibitor compound. In the present review, we first presented briefly the essence of CRLs' neddylation and its control, systematic analysis of CRLs, followed by the description of a few recorded chemical inhibitors of CRLs neddylation enzymes with recent examples of preclinical and clinical targets. We have also listed various structure-based pointing of protein-protein dealings in the CRLs' neddylation reaction, and last, the methods available to discover new inhibitors of neddylation are elaborated. This review will offer a concentrated, up-to-date, and detailed description of the discovery of neddylation inhibitors.
泛素连接酶E3家族中最大的组成部分是cullin-RING E3连接酶（CRLs），它们在因异常激活而引发的各种疾病中发挥着重要作用，尤其是在肿瘤发展过程中。CRLs的调控需要NEDD8化修饰，这是一种翻译后修饰，涉及一个酶促级联反应，该反应将小的、类泛素的NEDD8蛋白转移到CRLs上。许多先前的研究已证实NEDD8化修饰是抗癌药物研发中一个诱人的靶点，最近也有一些研究发现蛋白质NEDD8化修饰方面取得了显著进展，包括临床前和临床靶点验证以发现NEDD8化修饰抑制剂化合物。在本综述中，我们首先简要介绍了CRLs的NEDD8化修饰及其调控的本质，对CRLs进行了系统分析，接着描述了一些已记录的CRLs NEDD8化修饰酶的化学抑制剂，并列举了最近临床前和临床靶点的实例。我们还列出了CRLs的NEDD8化修饰反应中基于结构的各种蛋白质-蛋白质相互作用点，最后详细阐述了发现新的NEDD8化修饰抑制剂的可用方法。本综述将对NEDD8化修饰抑制剂的发现提供集中、最新且详细的描述。
