α/β-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.
α/β-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.
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DOI：
10.1021/jacs.5b05896
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发表时间：
2015-09-09
影响因子：
15
通讯作者：
Fairlie WD
中科院分区：
文献类型：
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作者：
Checco JW;Lee EF;Evangelista M;Sleebs NJ;Rogers K;Pettikiriarachchi A;Kershaw NJ;Eddinger GA;Belair DG;Wilson JL;Eller CH;Raines RT;Murphy WL;Smith BJ;Gellman SH;Fairlie WD
肽可被开发为蛋白质-蛋白质相互作用的有效拮抗剂，但常规肽（即，L-α-氨基酸的寡聚体）在体内受到显著的限制。由于快速的蛋白水解降解和不能穿过细胞膜而导致的短半衰期常常妨碍肽的生物应用。含有α-和β-氨基酸残基的寡聚体（“α/β-肽”）表现出对蛋白水解降解的敏感性降低，并且当适当设计时，这些非天然寡聚体可以模拟类似“α-肽”的蛋白质识别特性。本报告记录了α/β-肽方法的扩展，以靶向细胞内蛋白质-蛋白质相互作用。具体而言，我们已经基于“钉合”Bim BH 3 α-肽产生了α/β-肽，其含有烃交联以增强α-螺旋稳定性。我们表明，钉合α/β-肽可以在结构和功能上模拟母体钉合α-肽，其能够进入某些类型的细胞并阻断与凋亡信号相关的蛋白质-蛋白质相互作用。然而，α/β-肽对蛋白水解的抗性比母体α-肽高近100倍。这些结果表明，骨架修饰，一种在生物医学应用的肽工程方面受到相对较少关注的策略，可以与更常用的外周修饰如侧链交联组合以产生协同效益。
Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of L-α-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both α- and β-amino acid residues (“α/β-peptides”) manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous “α-peptides”. This report documents an extension of the α/β-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated α/β-peptides based on a “stapled” Bim BH3 α-peptide, which contains a hydrocarbon crosslink to enhance α-helix stability. We show that a stapled α/β-peptide can structurally and functionally mimic the parent stapled α-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the α/β-peptide is nearly 100-fold more resistant to proteolysis than is the parent α-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain crosslinking to produce synergistic benefits.