Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260-3000, USA.
J Am Chem Soc. 2012 Sep 12;134(36):14734-7. doi: 10.1021/ja306864v. Epub 2012 Sep 4.
Direct chemical modifications provide a simple and effective means to "translate" bioactive helical peptides into potential therapeutics targeting intracellular protein-protein interactions. We previously showed that distance-matching bisaryl cross-linkers can reinforce peptide helices containing two cysteines at the i and i+7 positions and confer cell permeability to the cross-linked peptides. Here we report the first crystal structure of a biphenyl-cross-linked Noxa peptide in complex with its target Mcl-1 at 2.0 Å resolution. Guided by this structure, we remodeled the surface of this cross-linked peptide through side-chain substitution and N-methylation and obtained a pair of cross-linked peptides with substantially increased helicity, cell permeability, proteolytic stability, and cell-killing activity in Mcl-1-overexpressing U937 cells.
直接的化学修饰提供了一种简单有效的方法，可以将具有生物活性的螺旋肽“转化”为针对细胞内蛋白质-蛋白质相互作用的潜在治疗药物。我们之前曾表明，距离匹配的双芳基交联剂可以增强含有两个半胱氨酸的 i 和 i+7 位的肽的螺旋，并赋予交联肽细胞通透性。在这里，我们报告了第一个与靶标 Mcl-1 结合的二苯基交联 Noxa 肽的晶体结构，分辨率为 2.0Å。受此结构的指导，我们通过侧链取代和 N-甲基化重塑了该交联肽的表面，并获得了一对交联肽，它们的螺旋度、细胞通透性、蛋白水解稳定性和对 Mcl-1 过表达 U937 细胞的杀伤活性都有显著提高。
