Tian Yuan, Jiang Yanhong, Li Jingxu, Wang Dongyuan, Zhao Hui, Li Zigang
Laboratory of Cytophysiology, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 611756, China.
Chembiochem. 2017 Nov 2;18(21):2087-2093. doi: 10.1002/cbic.201700352. Epub 2017 Sep 26.
Stapled peptides have emerged as a new class of targeting molecules with high binding affinity and specificity for intracellular undruggable targets. Their ability to penetrate cell membranes is exceptionally intriguing but remains elusively and controversially discussed. To understand the effect of stapling architectures on their physiochemical properties and to aid in promoting their cell permeability, we report herein a comparative study on the physiochemical properties and cell permeability of stapled α-helical peptides with different types of crosslinks. We highlight the decisive impact of the intrinsic properties of the crosslinks on cell permeability rather than the helical contents of the peptides in model amphipathic sequences targeting estrogen receptor-coactivator interaction. We envision this finding to shed further light on the chemical optimization of stapled α-helical peptides or macrocyclic cell-penetrating peptides for enhanced cell penetration.
钉合肽已成为一类新型靶向分子，对细胞内难以成药的靶点具有高结合亲和力和特异性。它们穿透细胞膜的能力格外引人关注，但关于这一能力的讨论仍然难以捉摸且存在争议。为了了解钉合结构对其物理化学性质的影响，并有助于提高其细胞通透性，我们在此报告了一项关于不同类型交联的钉合α-螺旋肽的物理化学性质和细胞通透性的比较研究。在针对雌激素受体-共激活因子相互作用的模型两亲性序列中，我们强调了交联的内在性质对细胞通透性的决定性影响，而非肽的螺旋含量。我们期望这一发现能为优化钉合α-螺旋肽或大环细胞穿透肽的化学结构以增强细胞穿透性提供更多启示。
