A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake.
A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake.
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双环肽支架促进磷酸酪氨酸模拟和细胞摄取。
DOI：
10.1016/j.bmc.2014.09.050
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发表时间：
2014
影响因子：
3.5
通讯作者：
Kritzer,JoshuaA
中科院分区：
文献类型：
--
作者：
Quartararo,JustinS;Eshelman,MatthewR;Peraro,Leila;Yu,Hongtao;Baleja,JamesD;Lin,Yu-Shan;Kritzer,JoshuaA
虽然肽作为探针和治疗剂是有前途的，但靶向细胞内蛋白质将需要对高度结构化的细胞内化支架有更深入的了解。我们最近发现了BC1，它是一种11个残基的双环肽，可抑制生长因子受体结合蛋白2（Grb 2）的Src同源2（SH 2）结构域。在这项工作中，我们描述了独特的结构和细胞吸收特性ofBC1和类似的环状和双环支架。这些受约束的支架被哺乳动物细胞吸收，尽管它们的净中性或负电荷，而不受约束的类似物则不然。摄取的机制是能量依赖性和内吞作用，但不同于达特。通过NMR和MD模拟研究了BC1的溶液结构，揭示了BC1上离散的水结合位点，减少了骨架酰胺对本体水的暴露。这代表了促进细胞摄取的原始和潜在的一般策略。
While peptides are promising as probes and therapeutics, targeting intracellular proteins will require greater understanding of highly structured, cell-internalized scaffolds. We recently reportedBC1, an 11-residue bicyclic peptide that inhibits the Src homology 2 (SH2) domain of growth factor receptor-bound protein 2 (Grb2). In this work, we describe the unique structural and cell uptake properties ofBC1and similar cyclic and bicyclic scaffolds. These constrained scaffolds are taken up by mammalian cells despite their net neutral or negative charges, while unconstrained analogs are not. The mechanism of uptake is shown to be energy-dependent and endocytic, but distinct from that of Tat. The solution structure ofBC1was investigated by NMR and MD simulations, which revealed discrete water-binding sites onBC1that reduce exposure of backbone amides to bulk water. This represents an original and potentially general strategy for promoting cell uptake.