Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.
Bioessays. 2022 Jan;44(1):e2100240. doi: 10.1002/bies.202100240. Epub 2021 Nov 23.
ADP-ribosylation is a post-translational modification catalyzed by writer enzymes - ADP-ribosyltransferases. The modification is part of many signaling events, can modulate the function and stability of target proteins, and often results in the recruitment of reader proteins that bind to the ADP-ribosyl groups. Erasers are integral actors in these signaling events and reverse the modification. ADP-ribosylation can be targeted with therapeutics and many inhibitors against writers exist, with some being in clinical use. Inhibitors against readers and erasers are sparser and development of these has gained momentum only in recent years. Drug discovery has been hampered by the lack of specific tools, however many significant advances in the methods have recently been reported. We discuss assays used in the field with a focus on methods allowing efficient identification of small molecule inhibitors and profiling against enzyme families. While human proteins are focused, the methods can be also applied to bacterial toxins and virus encoded erasers that can be targeted to treat infectious diseases in the future.
ADP-核糖基化是一种由writer 酶——ADP-核糖基转移酶催化的翻译后修饰。该修饰是许多信号事件的一部分，可以调节靶蛋白的功能和稳定性，并且通常导致结合 ADP-核糖基的 reader 蛋白的募集。erasers 是这些信号事件中的重要参与者，并可逆转修饰。ADP-核糖基化可以作为治疗的靶点，有许多针对writer 的抑制剂存在，其中一些已在临床应用。针对 reader 和 erasers 的抑制剂则较少，近年来这些抑制剂的开发才逐渐兴起。由于缺乏特异性工具，药物发现受到了阻碍，但最近在方法方面有了许多重大进展。我们讨论了该领域中使用的测定方法，重点介绍了能够有效鉴定小分子抑制剂并针对酶家族进行分析的方法。虽然重点是人类蛋白，但这些方法也可以应用于细菌毒素和病毒编码的 erasers，将来可以靶向这些 erasers 来治疗传染病。
