Melittin is a 26-amino acid amphiphilic alpha-helical peptide derived from honeybee venom. Prior studies have incorporated melittin into non-viral delivery systems to effect endosomal escape of DNA nanoparticles and improve transfection efficiency. Recent advances have led to the development of two newer melittin analogues, MelP5 and Macrolittin 70, with improved pore formation in lipid bilayers while possessing fewer positive charges relative to natural melittin. Consequently, MelP5 and Macrolittin 70 were conjugated through a disulfide bond to a DNA binding polyacridine peptide. The resulting peptide conjugates were used to prepare DNA nanoparticles to compare their relative endosomolytic potency by transfection of HepG2 cells. Melittin and MelP5 conjugates were equally potent at mediating in vitro gene transfer, whereas PEGylation of DNA nanoparticles revealed improved transfection with MelP5 relative to melittin. The results demonstrate the ability to substitute a potent, reduced-charge analogue of melittin to improve overall DNA nanoparticle biocompatibility needed for in vivo testing.

中文翻译：

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电荷减少的蜂毒肽类似物 MelP5 可改善非病毒 DNA 纳米颗粒的转染。


蜂毒肽是一种源自蜜蜂毒液的 26 个氨基酸两亲性 α 螺旋肽。先前的研究已将蜂毒肽纳入非病毒递送系统，以影响 DNA 纳米粒子的内体逃逸并提高转染效率。最近的进展导致了两种更新的蜂毒肽类似物 MelP5 和 Macrolittin 70 的开发，它们改善了脂质双层中的孔形成，同时相对于天然蜂毒肽具有更少的正电荷。因此，MelP5 和 Macrolittin 70 通过二硫键与 DNA 结合聚吖啶肽缀合。所得肽缀合物用于制备 DNA 纳米颗粒，通过转染 HepG2 细胞来比较它们的相对内体溶解效力。蜂毒肽和 MelP5 缀合物在介导体外基因转移方面同样有效，而 DNA 纳米颗粒的聚乙二醇化显示，与蜂毒肽相比，MelP5 的转染效果有所改善。结果表明，能够替代蜂毒肽的有效、电荷减少的类似物，以改善体内测试所需的整体 DNA 纳米粒子生物相容性。