Dipicolylamine/Metal Complexes that Promote Direct Cell-Membrane Penetration of Octaarginine
Dipicolylamine/Metal Complexes that Promote Direct Cell-Membrane Penetration of Octaarginine
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促进八精氨酸直接细胞膜渗透的二吡啶胺/金属络合物
DOI：
10.1021/acs.bioconjchem.8b00691
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Shiroh Futaki
中科院分区：
文献类型：
--
作者：
Yoshimasa Kawaguchi;Shoko Ise;Yusuke Azuma;Toshihide Takeuchi;Kenichi Kawano;Toan Khanh Le;Junko Ohkanda;Shiroh Futaki
通过将一个单一的2，2 ′-吡啶二甲基胺（DPA-R8）与金属离子形成1：1的络合物，可以显著促进细胞穿透肽八精氨酸（R8）的膜渗透。使用巨大的单层囊泡的研究表明，DPA的目标磷脂和增强R8的金属离子的存在下结合到膜。虽然DPA/Zn（II）络合物最常用于与磷酸盐形成螯合物，但Ni（II）对DPA-R8的膜结合和渗透具有最显著的影响。在Ni（II）的存在下，DPA-R8在几分钟内也获得了容易的胞质分布。DPA-R8/Ni（II）的细胞摄取方法的分析表明，不使用内吞作用，直接渗透通过细胞膜。使用拟肽法尼基转移酶抑制剂FTI 277举例说明了该系统对生物活性化合物的细胞内递送的适用性。
Marked promotion of membrane permeation of a cell-penetrating peptide, octaarginine (R8), was attained by attachment to a single 2,2′-dipicolylamine moiety (DPA-R8) that forms 1:1 complexes with metal ions. Studies using giant unilamellar vesicles demonstrated that DPA targets phospholipids and enhances R8 binding to the membranes in the presence of metal ions. While DPA/Zn(II) complex has been most frequently employed for chelate formation with phosphates, Ni(II) had the most prominent effect on the membrane binding and penetration of DPA-R8. Facile cytosolic distribution of DPA-R8 was also attained in a few minutes in the presence of Ni(II). Analysis of the cellular uptake methods of DPA-R8/Ni(II) suggested the involvement of direct permeation through cell membrane without the use of endocytosis. The applicability of this system to the intracellular delivery of bioactive compounds was exemplified using a peptidomimetic farnesyltransferase inhibitor, FTI277.