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首页> 外文期刊>Nucleic Acid Therapeutics >Modification of KL4 Peptide Revealed the Importance of Alpha-Helical Structure for Efficient Small Interfering RNA Delivery
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Modification of KL4 Peptide Revealed the Importance of Alpha-Helical Structure for Efficient Small Interfering RNA Delivery

机译：KL4肽的改性揭示了α-螺旋结构对高效小干扰RNA递送的重要性

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摘要

A safe and effective delivery system is considered a key to the success of nucleic acid therapeutics. It has been reported that pulmonary surfactants or their components could facilitate the uptake of small interfering RNA (siRNA) into the lung epithelial cells. Previously, our group investigated the use of KL4 peptide, a synthetic cationic peptide that simulates the structural properties of surfactant protein B (SP-B), as siRNA delivery vector. Although KL4 peptide exhibits good in vitro siRNA transfection efficiency on lung epithelial cells, its therapeutic potential is limited by its poor aqueous solubility due to the presence of a high proportion of hydrophobic leucine residues. In this study, we aim to address the solubility issue, designing five different modified peptides by replacing the hydrophobic leucine with alanine or valine, and assess their potential as siRNA delivery vectors. While the modified peptides retain the overall cationic property, their siRNA binding is also affected and their transfection efficiency is inferior to the parent KL4 peptide. A closer examination of the conformation of these peptides by circular dichroism shows that substitution of leucine residues leads to the change of the secondary structure from alpha-helical content to either beta-sheet or more disordered, beta-turn conformations. Relatively conservative amino acid substitutions, in terms of hydrophobicity bulk, lead to substantial conformational alteration, heavily impacting siRNA binding and release, cellular uptake, and transfection efficiency. Although the peptide modification strategy employed in this study was unsuccessful in developing an improved version of KL4 peptide for siRNA delivery, it highlights the importance of the alpha-helical conformation for efficient siRNA transfection, providing useful insights for future development of peptide-based RNA delivery system.
机译：安全有效的给药系统被认为是核酸治疗成功的关键。据报道，肺表面活性剂或其组分可促进小干扰RNA（siRNA）进入肺上皮细胞。在此之前，我们的团队研究了KL4肽作为siRNA载体的应用，这是一种模拟表面活性剂蛋白B（SP-B）结构特性的合成阳离子肽。尽管KL4肽在体外对肺上皮细胞表现出良好的siRNA转染效率，但由于存在高比例的疏水亮氨酸残基，其水溶性差，限制了其治疗潜力。在这项研究中，我们旨在解决溶解度问题，通过用丙氨酸或缬氨酸取代疏水性亮氨酸来设计五种不同的修饰肽，并评估它们作为siRNA载体的潜力。虽然修饰肽保留了整体阳离子性质，但它们的siRNA结合也受到影响，其转染效率低于亲本KL4肽。通过圆二色性对这些肽的构象进行更仔细的研究表明，亮氨酸残基的取代导致二级结构从α-螺旋含量改变为β-折叠或更无序的β-翻转构象。就疏水性而言，相对保守的氨基酸替换会导致大量构象改变，严重影响siRNA结合和释放、细胞摄取和转染效率。尽管本研究中采用的肽修饰策略未能成功开发用于siRNA递送的KL4肽的改良版本，但它强调了α螺旋构象对于有效siRNA转染的重要性，为基于肽的RNA递送系统的未来开发提供了有用的见解。

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