Amphiphilic Bicyclic Peptides as Cellular Delivery Agents
Amphiphilic Bicyclic Peptides as Cellular Delivery Agents
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DOI：
10.1002/cmdc.201402230
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发表时间：
2014-11-01
期刊：
影响因子：
3.4
通讯作者：
Parang, Keykavous
中科院分区：
文献类型：
--
作者：
Oh, Donghoon;Darwish, Shaban Anwar;Parang, Keykavous
从单环肽结构单元合成了由色氨酸和精氨酸残基组成的两个双环肽，并作为细胞递送剂进行评价。含有[W（5）G]-（三唑）-[KR 5]和[W5 E]-（-Ala）-[KR 5]的三唑和-丙氨酸接头分别将荧光素（F）标记的磷酸肽F-GpYEEI（F-PP）在人卵巢腺癌细胞中的细胞递送提高了7.6倍和19.3倍。然而，母体单环肽[R-5]和单环肽[WR]（4）仅分别将磷酸肽的细胞摄取增强仅1.3倍和3.7倍。共聚焦显微镜观察发现，荧光素标记的双环肽F-[KW 4 E]-（-Ala）-[KR 5]定位于胞浆和细胞核中。在胞吞抑制剂存在下研究F-[KW 4 E]-（-Ala）-[KR 5]的细胞摄取表明，网格蛋白和小窝蛋白依赖的胞吞是细胞摄取的主要途径。双环肽能够将阿霉素的抗增殖活性提高20%。这些数据表明，这种双环肽可用作一类新的细胞穿透肽和细胞递送工具。
Two bicyclic peptides composed of tryptophan and arginine residues were synthesized from monocyclic peptide building blocks and evaluated as cellular delivery agents. [W(5)G]-(triazole)-[KR5] and [W5E]-(-Ala)-[KR5] containing triazole and -alanine linkers improved the cellular delivery of fluorescein (F)-labeled phosphopeptide F-GpYEEI (F-PP) by 7.6- and 19.3-fold, respectively, in human ovarian adenocarcinoma cells. However, parent monocyclic peptide [R-5] and monocyclic peptide [WR](4) only enhanced the cellular uptake of the phosphopeptide by only 1.3- and 3.7-fold, respectively. Confocal microscopy showed that the corresponding fluorescein-labeled bicyclic peptide F-[KW4E]-(-Ala)-[KR5] was localized in the cytosol and nucleus. Studying the cellular uptake of F-[KW4E]-(-Ala)-[KR5] in the presence of endocytosis inhibitors indicated that the clathrin- and caveolin-dependent endocytosis are the main pathways for cellular uptake. The bicyclic peptide was able to improve antiproliferative activity of doxorubicin by 20%. These data suggest that this bicyclic peptide can be utilized as a new class of cell-penetrating peptides and cellular delivery tools.