Horikoshi Kanako, Miyamoto Maho, Tsuchiya Keisuke, Yokoo Hidetomo, Demizu Yosuke
National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki 210-9501, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Division of Pharmaceutical Organic Chemistry, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigakudori, Sanyo-Onoda-shi, Yamaguchi 756-0884, Japan.
Bioorg Med Chem. 2024 Sep 1;111:117871. doi: 10.1016/j.bmc.2024.117871. Epub 2024 Aug 8.
Cell-penetrating peptides (CPPs) are crucial for delivering macromolecules such as nucleic acids into cells. This study investigates the effectiveness of dual-modified penetratin peptides, focusing on the impact of stapling structures and an endosomal escape domain (EED) on enhancing intracellular uptake. Some CPPs were synthesized with an EED at either the N- or C-terminus and stapling structures, and then complexed with plasmid DNA (pDNA) to evaluate their cellular uptake. Results revealed that the combination of stapling and an EED significantly improved delivery efficiency, primarily via macropinocytosis and clathrin-mediated endocytosis. These findings underscore the importance of optimizing CPP sequences for effective nucleic acid delivery systems.
细胞穿透肽（CPPs）对于将核酸等大分子递送至细胞至关重要。本研究调查了双重修饰的穿膜肽的有效性，重点关注成环结构和内体逃逸结构域（EED）对增强细胞内摄取的影响。一些CPPs在N端或C端合成了EED并带有成环结构，然后与质粒DNA（pDNA）复合以评估其细胞摄取情况。结果显示，成环结构和EED的组合显著提高了递送效率，主要通过巨胞饮作用和网格蛋白介导的内吞作用实现。这些发现强调了优化CPP序列对于有效的核酸递送系统的重要性。
