A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action
A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action
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DOI：
10.1016/j.jconrel.2020.05.030
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发表时间：
2020-08-10
影响因子：
10.8
通讯作者：
Hristova, Kalina
中科院分区：
文献类型：
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作者：
Komin, Alexander;Bogorad, Maxim, I;Hristova, Kalina
小分子药物跨越生物屏障(如血脑屏障)的传输速度通常是实现治疗性剂量的限制因素。一种建议的策略是结合细胞穿透肽(CPPs)，以增强通过内皮或上皮单分子层的传递；然而，对于CPPs的设计用于有效的跨细胞转运，人们知之甚少。在这里，我们报告了一种名为CL肽的CPP的跨细胞转运，它使小分子货物通过模型上皮的转运增加了大约10倍。CL肽含有一个螺旋状基序和一个多聚精氨酸尾巴。我们研究了货物、螺旋状基序序列、多聚精氨酸尾长和多肽立体化学对货物交付的影响。我们发现存在一个最佳的螺旋状基序序列(RLLRLLR)和多聚精氨酸尾长(R7)用于货物传递。此外，我们证明了多肽-Cargo偶联物被上皮细胞在两个氨基酸连接物的位置切割。在转运出上皮之前，裂解将带有N-末端连接氨基酸的货物从多肽中释放出来。这些研究为开发用于跨细胞运送货物的新型CPP提供了新的序列要求。
The rate of transport of small molecule drugs across biological barriers, such as the blood-brain barrier, is often a limiting factor in achieving a therapeutic dose. One proposed strategy to enhance delivery across endothelial or epithelial monolayers is conjugation to cell-penetrating peptides (CPPs); however, very little is known about the design of CPPs for efficient transcellular transport. Here, we report on transcellular transport of a CPP, designated the CL peptide, that increases the delivery of small-molecule cargoes across model epithelium approximately 10-fold. The CL peptide contains a helix-like motif and a polyarginine tail. We investigated the effect of cargo, helix-like motif sequence, polyarginine tail length, and peptide stereochemistry on cargo delivery. We showed that there is an optimal helix-like motif sequence (RLLRLLR) and polyarginine tail length (R7) for cargo delivery. Furthermore, we demonstrated that the peptide-cargo conjugate is cleaved by cells in the epithelium at the site of a two-amino acid linker. The cleavage releases the cargo with the N-terminal linker amino acid from the peptide prior to transport out of the epithelium. These studies provide new insight into the sequence requirements for developing novel CPPs for transcellular delivery of cargo.