Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles.
Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles.
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DOI：
10.1186/s13619-015-0015-x
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
François M
中科院分区：
文献类型：
--
作者：
Fontaine F;Overman J;François M
在过去的30年里，人们对转录因子生物学及其遗传途径进行了大量研究，特别是在发育生物学和癌症领域。然而，我们对转录因子、基因组DNA和蛋白质伴侣之间高度动态相互作用的分子模式知之甚少。RNA-seq（RNA测序）、ChIP-seq（染色质免疫沉淀测序）、RIME（内源性蛋白质快速免疫沉淀质谱）和单分子成像等方法学突破将在未来几年内大大加快其分子作用模式的发现速度。从药理学的观点来看，用于用模拟内源性配体的分子靶向转录因子活性的常规方法不能实现高特异性，并且受到缺乏新分子靶标鉴定的限制。蛋白质-蛋白质相互作用可能代表下一个主要类别的治疗靶点之一。已知主要通过蛋白质-蛋白质相互作用起作用的转录因子很可能处于这种药物开发的最前沿。这一领域的一个障碍仍然是难以将结构数据整理成合理药物设计的有意义的信息。另一个障碍是缺乏满足蛋白质-蛋白质相互作用破坏的结构要求的化学文库。随着越来越多的调节转录因子活性的尝试，将积累有关调节转录所需的作用方式以及如何将这些发现应用于开发转录因子药物的有价值的知识。关键的发现将催生新的治疗方法，不仅作为抗癌靶点，还可用于其他适应症，如具有炎症成分的疾病，包括神经退行性疾病、糖尿病和慢性肝脏和肾脏疾病。
Much research on transcription factor biology and their genetic pathways has been undertaken over the last 30 years, especially in the field of developmental biology and cancer. Yet, very little is known about the molecular modalities of highly dynamic interactions between transcription factors, genomic DNA, and protein partners. Methodological breakthroughs such as RNA-seq (RNA-sequencing), ChIP-seq (chromatin immunoprecipitation sequencing), RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins), and single-molecule imaging will dramatically accelerate the discovery rate of their molecular mode of action in the next few years. From a pharmacological viewpoint, conventional methods used to target transcription factor activity with molecules mimicking endogenous ligands fail to achieve high specificity and are limited by a lack of identification of new molecular targets. Protein-protein interactions are likely to represent one of the next major classes of therapeutic targets. Transcription factors, known to act mostly via protein-protein interaction, may well be at the forefront of this type of drug development. One hurdle in this field remains the difficulty to collate structural data into meaningful information for rational drug design. Another hurdle is the lack of chemical libraries meeting the structural requirements of protein-protein interaction disruption. As more attempts at modulating transcription factor activity are undertaken, valuable knowledge will be accumulated on the modality of action required to modulate transcription and how these findings can be applied to developing transcription factor drugs. Key discoveries will spawn into new therapeutic approaches not only as anticancer targets but also for other indications, such as those with an inflammatory component including neurodegenerative disorders, diabetes, and chronic liver and kidney diseases.