Peptides with the multibasic cleavage site of the hemagglutinin from highly pathogenic influenza viruses act as cell-penetrating via binding to heparan sulfate and neuropilins.
Peptides with the multibasic cleavage site of the hemagglutinin from highly pathogenic influenza viruses act as cell-penetrating via binding to heparan sulfate and neuropilins.
复制标题
DOI：
10.1016/j.bbrc.2019.03.068
复制
发表时间：
2019-05
影响因子：
3.1
通讯作者：
Yasuyuki Yamamoto;Shigeyuki Tamiya;Meito Shibuya;I. Nakase;Y. Yoshioka
中科院分区：
文献类型：
--
作者：
Yasuyuki Yamamoto;Shigeyuki Tamiya;Meito Shibuya;I. Nakase;Y. Yoshioka
细胞穿透肽（CPPs）作为一种有吸引力的药物载体，可以将核酸、肽、蛋白质甚至颗粒等药物分子导入多种细胞类型。识别新的CPP并为每个应用选择最佳CPP是重要的，因为CPP在其内化效率和内化机制方面不同。在这里，我们确定了新的CPP来自肽的血凝素裂解位点（pHACS）的高致病性流感病毒。我们比较了来自甲型流感病毒的四种亚型（H1、H3、H5和H7）和B流感病毒的pHACS（分别为H1-pHACS、H3-pHACS、H5-pHACS、H7-pHACS和B-pHACS）的肽用作CPP的潜力。H5-pHACS和H7-pHACS，而不是其他肽，与小鼠树突细胞和人上皮细胞结合，并被有效地内化到这些细胞中。H5-pHACS和H7-pHACS需要糖胺聚糖，特别是硫酸乙酰肝素和神经纤毛蛋白，与细胞结合。此外，我们通过改变单个氨基酸设计了具有上级细胞结合能力的突变体H7-pHACS。此外，当与抗原缀合时，H5-pHACS和H7-pHACS诱导抗原特异性抗体应答，证明了这种抗原递送载体的有用性。我们的研究结果将提高我们对CPP机制的理解，并促进旨在提高治疗效果的新型药物递送载体的开发。
Cell-penetrating peptides (CPPs) show promise as an attractive delivery vehicle for therapeutic molecules—including nucleic acids, peptides, proteins, and even particulates—into several cell types. It is important to identify new CPPs and select the optimal CPP for each application, because CPPs differ in their internalized efficiency and internalization mechanisms. Here, we identified new CPPs derived from the peptides with the hemagglutinin cleavage site (pHACS) of highly pathogenic influenza viruses. We compared the potential of peptides from the pHACS of four subtypes of influenza A virus (H1, H3, H5, and H7) and an influenza B virus (H1-pHACS, H3-pHACS, H5-pHACS, H7-pHACS, and B-pHACS, respectively) to serve as CPPs. H5-pHACS and H7-pHACS, but not the other peptides, bound to mouse dendritic cells and human epithelial cells and were internalized efficiently into these cells. H5-pHACS and H7-pHACS required glycosaminoglycans, especially heparan sulfate and neuropilins, to bind to the cells. In addition, we designed a mutant H7-pHACS with superior cell-binding capability by changing a single amino acid. Furthermore, when conjugated with antigen, H5-pHACS and H7-pHACS induced antigen-specific antibody responses, demonstrating the usefulness of this antigen-delivery vehicle. Our results will improve our understanding of the mechanisms of CPPs and facilitate the development of novel drug-delivery vehicles designed to improve therapeutic efficacy.