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用于磷酸肽细胞递送的三脚架肽类似物的合成与评价

Synthesis and evaluation of tripodal peptide analogues for cellular delivery of phosphopeptides.

作者信息

Ye Guofeng, Nam Nguyen-Hai, Kumar Anil, Saleh Ali, Shenoy Dinesh B, Amiji Mansoor M, Lin Xiaofeng, Sun Gongqin, Parang Keykavous

机构信息

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.

出版信息

J Med Chem. 2007 Jul 26;50(15):3604-17. doi: 10.1021/jm070416o. Epub 2007 Jun 20.

DOI:10.1021/jm070416o
PMID:17580848
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2539070/
Abstract

Tripodal peptide analogues were designed on the basis of the phosphotyrosine binding pocket of the Src SH2 domain and assayed for their ability to bind to fluorescein-labeled phosphopeptides. Fluorescence polarization assays showed that a number of amphipathic linear peptide analogues (LPAs), such as LPA4, bind to fluorescein-labeled GpYEEI (F-GpYEEI). LPA4 was evaluated for potential application in cellular delivery of phosphopeptides. Fluorescence microimaging cellular uptake studies with fluorescein-attached LPA4 (F-LPA4) alone or with the mixture of LPA4 and F-GpYEEI in BT-20 cells showed dramatic increase of the fluorescence intensity in cytosol of cells, indicating that LPA4 can function as a delivery tool of F-GpYEEI across the cell membrane. Fluorescent flow cytometry studies showed the cellular uptake of F-LPA4 in an energy-independent pathway and confirmed the cellular uptake of F-GpYEEI in the presence of LPA4. These studies suggest that amphipathic tripodal peptide analogues, such as LPA4, can be used for cellular delivery of phosphopeptides.

摘要

基于Src SH2结构域的磷酸酪氨酸结合口袋设计了三脚架肽类似物，并检测了它们与荧光素标记的磷酸肽结合的能力。荧光偏振分析表明，许多两亲性线性肽类似物（LPA），如LPA4，可与荧光素标记的GpYEEI（F-GpYEEI）结合。对LPA4在磷酸肽细胞递送中的潜在应用进行了评估。在BT-20细胞中，单独使用荧光素标记的LPA4（F-LPA4）或LPA4与F-GpYEEI的混合物进行荧光显微成像细胞摄取研究，结果显示细胞胞质溶胶中的荧光强度显著增加，这表明LPA4可作为F-GpYEEI跨细胞膜的递送工具。荧光流式细胞术研究表明，F-LPA4通过能量非依赖途径被细胞摄取，并证实了在LPA4存在的情况下F-GpYEEI也能被细胞摄取。这些研究表明，两亲性三脚架肽类似物，如LPA4，可用于磷酸肽的细胞递送。

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