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首页> 外文期刊>Biochemistry >Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Allows Effective Cytosolic Cargo Delivery
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Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Allows Effective Cytosolic Cargo Delivery

机译：循环细胞穿透肽的早期内体逸出允许有效的胞质货运。

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摘要

Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR_4, where Φ is L-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR_4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR_4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR_4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR_4 was 4?12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR_4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape.
机译：最近发现，环状七肽环（FΦRRRRQ）（cFΦR_4，其中Φ为L-2-萘丙氨酸）可被哺乳动物细胞有效内化。在这项研究中，通过引入药理剂和基因突变来扰乱各种内吞事件，研究了其内在化机理。结果表明，cFΦR_4直接与膜磷脂结合，通过内吞作用被内化到人类癌细胞中，并从早期的内体逃逸到细胞质中。用各种分子检查了其货物容量，包括小分子染料，各种带电状态的线性和环状肽以及蛋白质。根据货物的性质，它们可以通过内环传递（将货物插入cFΦR_4环），外环传递（将货物连接到Gln侧链）或双环传递（将cFΦR_4和环状载货环融合）来交付。 cFΦR_4的总体递送效率（即，将货物递送到细胞质和细胞核中）比非精氨酸，HIV Tat衍生肽或渗透素的总递送效率高4-12倍。较高的递送效率，加上优异的血清稳定性，最小的毒性和合成的可及性，使cFΦR_4成为细胞内货物递送的有用转运蛋白和研究内体逃逸机理的合适系统。

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