Arginine-rich cell penetrating peptides: Design, structure-activity, and applications to alter pre-mRNA splicing by steric-block oligonucleotides
Arginine-rich cell penetrating peptides: Design, structure-activity, and applications to alter pre-mRNA splicing by steric-block oligonucleotides
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DOI：
10.1002/psc.979
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发表时间：
2008-04-01
影响因子：
2.1
通讯作者：
Lebleu, B.
中科院分区：
文献类型：
--
作者：
Abes, R.;Arzumanov, A.;Lebleu, B.
用空间嵌段寡核苷酸（ON）重新设计剪接机制可能会带来治疗β地中海贫血、杜氏肌营养不良症或癌症等疾病的新治疗策略。干扰剪接需要将 RNase H 无能力的 ON 作为肽核酸 (PNA) 或磷酸二酰胺吗啉寡聚物 (PMO) 进行序列特异性和稳定杂交。不幸的是，这些不带电荷的 DNA 模拟物很难被大多数细胞类型吸收，并且依赖静电相互作用的传统递送策略并不适用。同样，与 Tat、Arg(9)、Lys(8) 或 Pen 等细胞穿透肽 (CPP) 缀合会导致低浓度下剪接校正效率较差，这主要是因为 PNA- 和 PMO-CPP 缀合物仍被捕获在内吞囊泡内。最近，我们设计了一种富含精氨酸的肽（R-Ahx-R）（4）（Ahx代表氨基己酸）和一种精氨酸尾的Penetratin衍生物，它们可以在不存在内涵体溶解剂的情况下在低浓度下进行序列特异性和有效的剪接校正。两种 CPP 正在进行结构-活性关系研究，以进一步优化作为立体块 ON 递送载体。版权所有 (c) 2008 欧洲肽协会和 John Wiley & Sons。有限公司
Rerouting the splicing machinery with steric-block oligonucleotides (ON) might lead to new therapeutic strategies in the treatment of diseases such as beta-thalassemia, Duchenne muscular dystrophy, or cancers. Interfering with splicing requires the sequence-specific and stable hybridization of RNase H-incompetent ON as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligomers (PMO). Unfortunately, these uncharged DNA mimics are poorly taken up by most cell types and conventional delivery strategies that rely on electrostatic interaction do not apply. Likewise, conjugation to cell penetrating peptides (CPPs) as Tat, Arg(9), Lys(8), or Pen leads to poor splicing correction efficiency at low concentration essentially because PNA- and PMO-CPP conjugates remain entrapped within endocytotic vesicles. Recently, we have designed an arginine-rich peptide (R-Ahx-R)(4) (with Ahx for aminohexanoic acid) and an arginine-tailed Penetratin derivative which allow sequence-specific and efficient splicing correction at low concentration in the absence of endosomolytic agents. Both CPPs are undergoing structure-activity relationship studies for further optimization as steric-block ON delivery vectors. Copyright (c) 2008 European Peptide Society and John Wiley & Sons. Ltd.