EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Darlinghurst, New South Wales, Australia.
Nat Rev Drug Discov. 2024 Oct;23(10):759-779. doi: 10.1038/s41573-024-01025-z. Epub 2024 Sep 4.
Most protein-coding genes produce multiple protein isoforms; however, these isoforms are commonly neglected in drug discovery. The expression of protein isoforms can be specific to a disease, tissue and/or developmental stage, and this specific expression can be harnessed to achieve greater drug specificity than pan-targeting of all gene products and to enable improved treatments for diseases caused by aberrant protein isoform production. In recent years, several protein isoform-centric therapeutics have been developed. Here, we collate these studies and clinical trials to highlight three distinct but overlapping modes of action for protein isoform-centric drugs: isoform switching, isoform introduction or depletion, and modulation of isoform activity. In addition, we discuss how protein isoforms can be used clinically as targets for cell type-specific drug delivery and immunotherapy, diagnostic biomarkers and sources of cancer neoantigens. Collectively, we emphasize the value of a focus on isoforms as a route to discovering drugs with greater specificity and fewer adverse effects. This approach could enable the targeting of proteins for which pan-inhibition of all isoforms is toxic and poorly tolerated.
大多数蛋白编码基因产生多种蛋白亚型；然而，这些亚型在药物发现中通常被忽视。蛋白亚型的表达可能是特定于疾病、组织和/或发育阶段的，这种特异性表达可以被利用来实现比针对所有基因产物的泛靶向更高的药物特异性，并为异常蛋白亚型产生引起的疾病提供更好的治疗方法。近年来，已经开发了几种以蛋白亚型为中心的治疗方法。在这里，我们汇集了这些研究和临床试验，以突出以蛋白亚型为中心的药物的三种不同但重叠的作用模式：亚型转换、亚型引入或耗尽，以及亚型活性的调节。此外，我们还讨论了如何将蛋白亚型用作细胞类型特异性药物递送和免疫疗法、诊断生物标志物和癌症新抗原来源的临床靶点。总的来说，我们强调关注亚型作为发现具有更高特异性和更少副作用的药物的途径的价值。这种方法可以针对所有亚型的泛抑制都具有毒性和耐受性差的蛋白。
