Lazar Tamas, Connor Acadia, DeLisle Charles F, Burger Virginia, Tompa Peter
VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium.
Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Nat Rev Drug Discov. 2025 Jun 9. doi: 10.1038/s41573-025-01220-6.
Intrinsically disordered proteins have key signalling and regulatory roles in cells and are frequently dysregulated in diseases such as cancer, neurodegeneration, inflammation and autoimmune disorders. Preventing the pathological functions mediated by structural disorder is crucial to successfully target proteins that drive transcription, biomolecular condensation and protein aggregation. However, owing to their heterogeneous, highly dynamic structural states, with ensembles of rapidly interconverting conformations, disordered proteins have been considered largely 'undruggable' by traditional approaches. Here, we review key developments of the field and suggest that the synergy of advanced experimental and computational approaches needs to be pursued to conquer this barrier in drug discovery.
内在无序蛋白质在细胞中具有关键的信号传导和调节作用，并且在诸如癌症、神经退行性疾病、炎症和自身免疫性疾病等病症中经常失调。阻止由结构无序介导的病理功能对于成功靶向驱动转录、生物分子凝聚和蛋白质聚集的蛋白质至关重要。然而，由于其异质的、高度动态的结构状态，以及快速相互转化的构象集合，传统方法在很大程度上认为无序蛋白质是“不可成药的”。在这里，我们回顾了该领域的关键进展，并提出需要采用先进的实验和计算方法的协同作用来克服药物发现中的这一障碍。
