Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, LS2 9JT, United Kingdom.
Essays Biochem. 2022 Dec 16;66(7):959-975. doi: 10.1042/EBC20220046.
The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with a range of human pathologies, including neurodegeneration, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds of millions of people worldwide, and the number of people affected is increasing sharply. However, the discovery of therapeutic agents has been immensely challenging largely because of (i) the diverse number of aggregation pathways and the multi-conformational and transient nature of the related proteins or peptides and (ii) the under-development of experimental pipelines for the identification of disease-modifying molecules and their mode-of-action. Here, we describe current approaches used in the search for small-molecule modulators able to control or arrest amyloid formation commencing from IDPs and review recently reported accelerators and inhibitors of amyloid formation for this class of proteins. We compare their targets, mode-of-action and effects on amyloid-associated cytotoxicity. Recent successes in the control of IDP-associated amyloid formation using small molecules highlight exciting possibilities for future intervention in protein-misfolding diseases, despite the challenges of targeting these highly dynamic precursors of amyloid assembly.
无规卷曲蛋白/肽（IDPs）病理性聚集形成淀粉样纤维与一系列人类病理相关，包括神经退行性疾病、代谢疾病和系统性淀粉样变性。这些使人衰弱的疾病影响着全球数以亿计的人群，且受影响的人数正在急剧增加。然而，治疗药物的发现极具挑战性，主要是因为：(i) 聚集途径多种多样，相关蛋白或肽具有多构象和瞬态性质；(ii) 用于鉴定具有疾病修饰作用的分子及其作用模式的实验方案还不够完善。在这里，我们描述了当前用于寻找能够控制或阻止起始于 IDPs 的淀粉样形成的小分子调节剂的方法，并综述了最近报道的用于此类蛋白质的淀粉样形成的促进剂和抑制剂。我们比较了它们的靶点、作用模式和对淀粉样相关细胞毒性的影响。尽管靶向这些高度动态的淀粉样组装前体具有挑战性，但使用小分子控制 IDP 相关淀粉样形成的最新成功为蛋白质错误折叠疾病的未来干预提供了令人兴奋的可能性。
