蛋白质同工型中心疗法：扩大靶标和提高特异性
Protein isoform-centric therapeutics: expanding targets and increasing specificity
影响因子:101.80000
分区:医学1区 Top / 生物工程与应用微生物1区 药学1区
发表日期:2024 Oct
作者:
Peter Kjer-Hansen, Tri Giang Phan, Robert J Weatheritt
摘要
大多数蛋白质编码基因产生多种蛋白质同工型。但是，这些同工型通常在药物发现中被忽略。蛋白质同工型的表达可以特定于疾病，组织和/或发育阶段，并且可以利用该特异性表达来实现与所有基因产物的泛靶标的更高的药物特异性，并能够改善由异常蛋白质同工型产生引起的疾病的治疗方法。近年来，已经开发了几种以蛋白质同工型为中心的疗法。在这里，我们整理了这些研究和临床试验，以突出三种以蛋白质同工型药物的不同但重叠的作用方式：同工型转换，同工型引入或耗尽以及同工型活性的调节。此外，我们讨论了如何在临床上使用蛋白质同工型作为细胞类型的药物递送和免疫疗法，诊断生物标志物和癌症新抗原的来源的靶标。总体而言，我们强调了对同工型的重点的价值，这是发现具有更特异性和更少不良影响的药物的途径。这种方法可以使蛋白质的靶向所有同工型的泛块抑制蛋白质有毒且耐受性不佳。
Abstract
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.