Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide
Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide
复制标题
使用环状细胞穿透肽增强钉合肽的细胞渗透性
DOI：
10.1021/acs.jmedchem.9b00456
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发表时间：
2019-11-28
影响因子：
7.3
通讯作者：
Pei, Dehua
中科院分区：
文献类型：
--
作者：
Dougherty, Patrick G.;Wen, Jin;Pei, Dehua
钉合肽概括了蛋白质中α螺旋的结合亲和力和特异性，抵抗蛋白水解降解，并可能提供一种针对具有挑战性的药物靶点（例如蛋白质-蛋白质相互作用）的新方式。然而，大多数钉合肽的细胞渗透性有限或对细胞膜不可渗透。我们在此表明，通过将环状细胞穿透肽缀合至其N末端、C末端或钉合单元，可以使钉合肽具有高度细胞渗透性。将该策略应用于之前报道的两种针对 MDM2/p53 和 β-catenin/TCF 相互作用的膜不可渗透的肽基抑制剂，产生了针对关键治疗靶点的有效概念验证抗增殖药物。
Stapled peptides recapitulate the binding affinity and specificity of a-helices in proteins, resist proteolytic degradation, and may provide a novel modality against challenging drug targets such as protein-protein interactions. However, most of the stapled peptides have limited cell permeability or are impermeable to the cell membrane. We show herein that stapled peptides can be rendered highly cell-permeable by conjugating a cyclic cell-penetrating peptide to their N-terminus, C-terminus, or stapling unit. Application of this strategy to two previously reported membrane-impermeable peptidyl inhibitors against the MDM2/p53 and beta-catenin/TCF interactions resulted in the generation of potent proof-of-concept antiproliferative agents against key therapeutic targets.