Department of Chemistry and Division of Advanced Material Science, Pohang University of Science and Technology (POSTECH) , Pohang 37673, South Korea.
New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation , Daegu 41061, South Korea.
J Am Chem Soc. 2017 Nov 15;139(45):16056-16059. doi: 10.1021/jacs.7b08972. Epub 2017 Nov 1.
The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.
转录因子 (TFs) 和共激活蛋白之间的复杂形成是转录活性所必需的，因此，破坏异常激活的 TF/共激活蛋白相互作用可能是一种有吸引力的治疗策略。然而，这种蛋白质-蛋白质相互作用 (PPI) 的调节已被证明具有挑战性。在这里，我们报告了一种细胞渗透性、蛋白水解稳定的订书肽，它直接靶向核受体共激活因子 1 (NCOA1)，NCOA1 是信号转导和转录激活因子 6 (STAT6) 转录活性所必需的共激活因子。我们证明，这种订书肽破坏了 NCOA1/STAT6 复合物，从而抑制了 STAT6 介导的转录。此外，我们解决了第一个与 NCOA1 形成复合物的订书肽的晶体结构。因此，订书肽代表了一种非常有价值的化学探针，用于理解 NCOA1/STAT6 相互作用的确切作用，也是开发一类新型治疗剂的绝佳起点。
