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首页> 外文期刊>Advanced Functional Materials >Supramolecular Assembly of Aminoethylene-Lipopeptide PMO Conjugates into RNA Splice-Switching Nanomicelles
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Supramolecular Assembly of Aminoethylene-Lipopeptide PMO Conjugates into RNA Splice-Switching Nanomicelles

机译：氨基乙烯-脂肽PMO的超分子组装缀合到RNA拼接转换Nanomicelles。

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摘要

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre-mRNA splicing. Similar to other classes of nucleic acid-based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl-tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain-promoted azide-alkyne cycloaddition conjugation with splice-switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice-switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K-mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice-switching at very low nanomolar concentrations. The presented aminoethylene-lipopeptides are thus a promising platform for the generation of PMO-therapeutics with a favorable activity/toxicity profile.
机译：磷酸二氨基甲酸酯吗啉代寡聚物（PMO）是寡核苷酸类似物，可用于治疗性调制mRNA前剪接。类似于其他类别的基于核酸的治疗剂，PMO需要用于有效转运至细胞内靶位点的递送系统。在这里，提出了基于低聚（亚乙基氨基酸）琥珀酰-四亚乙基五胺（Stp），疏水性修饰和叠氮基的人工肽，它们可用于通过应变转换PMO进行菌株促进的叠氮化物-炔烃环加成偶联。通过系统地改变前导结构和制剂，可以确定所含脂肪酸的类型和超分子组装对递送功效具有关键影响。包含具有三个顺式双键的亚麻酸的化合物在体外和体内局部给药后，在pLuc / 705报告分子细胞中表现出最高的剪接转换活性，并显着提高功能蛋白的表达。结构和机理研究表明，脂肽PMO共轭物形成纳米颗粒，可加速细胞摄取，不饱和脂肪酸的含量可增强内体逃逸。在使用H2K-mdx52营养不良性骨骼肌管的体外杜氏肌营养不良外显子跳跃模型中，高效PMO缀合物在非常低的纳摩尔浓度下介导了显着的剪接转换。因此，所提出的氨基乙烯-脂肽是用于产生具有有利活性/毒性特征的PMO治疗剂的有前途的平台。

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