以蛋白质亚型为中心的治疗策略：拓宽靶点并提高特异性
Protein isoform-centric therapeutics: expanding targets and increasing specificity
DOI 原文链接
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影响因子:101.8
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
DOI:
10.1038/s41573-024-01025-z
摘要
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常被忽视。蛋白亚型的表达可能具有特异性，依赖于疾病、组织和/或发育阶段，这种特异性表达可以被利用，以实现比全基因产物靶向更高的药物特异性，并改善由异常蛋白亚型产生引起的疾病治疗。近年来，已经开发出多种以蛋白亚型为核心的治疗药物。本文整理了这些研究和临床试验，强调蛋白亚型药物的三种主要作用方式：亚型转换、亚型引入或耗竭，以及亚型活性的调控。此外，我们还探讨了蛋白亚型在临床中作为靶点，用于细胞类型特异性药物递送、免疫治疗、诊断生物标志物和癌症新抗原的潜在用途。总体而言，强调关注亚型作为发现更具特异性和较少副作用药物的途径。这一策略有助于靶向那些全抑制所有亚型会带来毒性和耐受性差的蛋白质。
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.