Department of Chemistry, New York University, New York, New York 10003, USA.
J Am Chem Soc. 2010 Jan 27;132(3):941-3. doi: 10.1021/ja9082864.
Designed ligands that inhibit hypoxia-inducible gene expression could offer new tools for genomic research and, potentially, drug discovery efforts for the treatment of neovascularization in cancers. We report a stabilized alpha-helix designed to target the binding interface between the C-terminal transactivation domain (C-TAD) of hypoxia-inducible factor 1alpha (HIF-1alpha) and cysteine-histidine rich region (CH1) of transcriptional coactivator CBP/p300. The synthetic helix disrupts the structure and function of this complex, resulting in a rapid downregulation of two hypoxia-inducible genes (VEGF and GLUT1) in cell culture.
设计抑制低氧诱导基因表达的配体可为基因组研究提供新的工具，并可能为癌症中新生血管形成的治疗提供药物发现的潜力。我们报告了一种稳定的α-螺旋的设计，该设计针对缺氧诱导因子 1α（HIF-1α）的 C 端反式激活结构域（C-TAD）与转录共激活因子 CBP/p300 的半胱氨酸-组氨酸丰富区（CH1）之间的结合界面。该合成螺旋破坏了该复合物的结构和功能，导致细胞培养中两种缺氧诱导基因（VEGF 和 GLUT1）的快速下调。
