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分支型、富含精氨酸的肽树枝状聚合物缀合物与肽核酸寡核苷酸的合成及剪接重定向活性。

Synthesis and splice-redirecting activity of branched, arginine-rich peptide dendrimer conjugates of peptide nucleic acid oligonucleotides.

机构信息

Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.

出版信息

Bioconjug Chem. 2010 Oct 20;21(10):1902-11. doi: 10.1021/bc100275r.

DOI:10.1021/bc100275r
PMID:20879728
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2963316/
Abstract

Arginine-rich cell-penetrating peptides have found excellent utility in cell and in vivo models for enhancement of delivery of attached charge-neutral PNA or PMO oligonucleotides. We report the synthesis of dendrimeric peptides containing 2- or 4-branched arms each having one or more R-Ahx-R motifs and their disulfide conjugation to a PNA705 splice-redirecting oligonucleotide. Conjugates were assayed in a HeLa pLuc705 cell assay for luciferase up-regulation and splicing redirection. Whereas 8-Arg branched peptide-PNA conjugates showed poor activity compared to a linear (R-Ahx-R)(4)-PNA conjugate, 2-branched and some 4-branched 12 and 16 Arg peptide-PNA conjugates showed activity similar to that of the corresponding linear peptide-PNA conjugates. Many of the 12- and 16-Arg conjugates retained significant activity in the presence of serum. Evidence showed that biological activity in HeLa pLuc705 cells of the PNA conjugates of branched and linear (R-Ahx-R) peptides is associated with an energy-dependent uptake pathway, predominantly clathrin-dependent, but also with some caveolae dependence.

摘要

富含精氨酸的细胞穿透肽在细胞和体内模型中被广泛应用于增强带电荷中性 PNA 或 PMO 寡核苷酸的传递。我们报告了含有 2 或 4 个分支臂的树状肽的合成，每个臂都有一个或多个 R-Ahx-R 基序，并将其与 PNA705 剪接重定向寡核苷酸进行二硫键连接。在 HeLa pLuc705 细胞测定中，对缀合物进行了荧光素酶上调和剪接重定向的检测。与线性（R-Ahx-R）（4）-PNA 缀合物相比，8-Arg 分支肽-PNA 缀合物的活性较差，而 2-分支和一些 4-分支的 12 和 16 Arg 肽-PNA 缀合物的活性与相应的线性肽-PNA 缀合物相似。许多 12-和 16-Arg 缀合物在存在血清的情况下仍保持显著的活性。证据表明，HeLa pLuc705 细胞中分支和线性（R-Ahx-R）肽的 PNA 缀合物的生物学活性与能量依赖性摄取途径有关，主要是网格蛋白依赖性，但也有一些小窝依赖性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/60f478371e27/bc-2010-00275r_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/8c93a6beb138/bc-2010-00275r_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/2fa4c02c5a94/bc-2010-00275r_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/60f478371e27/bc-2010-00275r_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/8c93a6beb138/bc-2010-00275r_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/2fa4c02c5a94/bc-2010-00275r_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/25b8/2963316/60f478371e27/bc-2010-00275r_0006.jpg

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