Design and Evaluation of Histidine-Rich Amphipathic Peptides for siRNA Delivery
Design and Evaluation of Histidine-Rich Amphipathic Peptides for siRNA Delivery
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DOI：
10.1007/s11095-010-0138-2
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发表时间：
2010-07-01
影响因子：
3.7
通讯作者：
Kichler, Antoine
中科院分区：
文献类型：
--
作者：
Langlet-Bertin, Berangere;Leborgne, Christian;Kichler, Antoine
短线性多肽具有很高的潜力，可以输送包括核酸在内的各种具有治疗潜力的药物。最近，我们发现富含组氨酸的阳离子两亲性多肽LAH4(KKALLALHLAHLAHLALKA)具有很高的DNA递送能力。由于这些多肽被认为可以有效地干扰内膜，我们测试了它们将小干扰RNA(SiRNA)运送到哺乳动物细胞的能力。使用稳定转染荧光素酶编码表达载体的人细胞系，我们评估了LAH4及其五个衍生物传递siRNA和沉默基因表达的能力。这六个多肽都是有效的siRNA载体，它们在介导911-Luc细胞基因沉默方面的效率高于商业化合物，包括脂质体胺、DOTAP和聚乙烯亚胺。此外，通过使用质子泵抑制剂巴菲尔霉素A1，我们发现有效的siRNA传递到胞浆需要内体的酸化。富含LAH4组氨酸的阳离子两亲性多肽代表了一类有趣的和有前途的siRNA传递化合物家族。
Short linear peptides have a high potential for delivering various drugs with therapeutic potential, including nucleic acids. Recently, we have shown that the cationic amphipathic histidine-rich peptide LAH4 (KKALLALALHHLAHLALHLALALKKA) possesses high plasmid DNA delivery capacities. Since such peptides are thought to efficiently disrupt endosomal membranes, we have tested their ability to deliver small interfering RNA (siRNA) into mammalian cells.Using a human cell line stably transfected with a luciferase-encoding expression vector, we have evaluated the ability of LAH4 and five derivatives thereof to deliver siRNAs and silence gene expression.The six peptides are all efficient siRNA delivery vehicles whose efficiency in mediating gene silencing in 911-Luc cells was greater than that of commercially available compounds including Lipofectamine, DOTAP and polyethylenimine. In addition, by using the proton pump inhibitor bafilomycin A1, we show that efficient siRNA delivery to the cytosol requires acidification of the endosomes.The LAH4 histidine-rich cationic amphipathic peptides represent an interesting and promising family of compounds for siRNA delivery.