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.

大多数蛋白质编码基因产生多种蛋白质亚型;然而，这些亚型在药物发现中通常被忽视。蛋白质亚型的表达可以针对疾病、组织和/或发育阶段具有特异性，并且可以利用这种特异性表达来实现比所有基因产物的泛靶向更高的药物特异性，并能够改进由异常蛋白质亚型产生引起的疾病的治疗。近年来，已经开发了几种以蛋白质亚型为中心的疗法。在这里，我们整理了这些研究和临床试验，以强调以蛋白质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、亚型引入或耗竭以及亚型活性的调节。此外，我们还讨论了蛋白质亚型如何在临床上用作细胞类型特异性药物递送和免疫治疗的靶标、诊断生物标志物和癌症新抗原的来源。总的来说，我们强调关注亚型的价值，作为发现具有更高特异性和更少不良反应的药物的途径。这种方法可以靶向所有亚型的泛抑制具有毒性且耐受性差的蛋白质。