Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Chem Soc Rev. 2011 Aug;40(8):4286-94. doi: 10.1039/c1cs15050b. Epub 2011 Jun 23.
The human body is comprised of several hundred distinct cell types that all share a common genomic template. This diversity arises from regulated expression of individual genes. The first critical step in this process is transcription and is governed by a large number of transcription factors. Small molecules that can alter transcription hold tremendous utility as chemical probes and therapeutics. To fully realize their potential, however, artificial transcription factors must be able to orchestrate protein recruitment at gene promoters just like their natural counterparts. This tutorial review surveys the discovery of small ligands (drug-like molecules and short peptides) that bind transcriptional coregulatory proteins, and thus comprise one of the two essential characteristics of a transcription factor. By joining these ligands to DNA-targeting moieties, one can construct a bifunctional molecule that recruits its protein target to specific genes and controls gene transcription.
人体由数百种不同的细胞类型组成，这些细胞类型都共享一个共同的基因组模板。这种多样性源于单个基因的调节表达。这个过程的第一步是转录，它由大量转录因子控制。能够改变转录的小分子作为化学探针和治疗药物具有巨大的效用。然而，为了充分发挥其潜力，人工转录因子必须能够像天然转录因子一样在基因启动子处协调蛋白质募集。本教程综述了发现与转录共调节蛋白结合的小分子配体（类药物分子和短肽）的情况，这些小分子配体构成了转录因子的两个基本特征之一。通过将这些配体与 DNA 靶向部分结合，可以构建一种双功能分子，将其蛋白质靶标募集到特定基因并控制基因转录。
