Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death.
Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death.
复制标题
DOI：
10.1016/j.ejmech.2018.01.045
复制
发表时间：
2018-02
影响因子：
6.7
通讯作者：
Makoto Tanaka;Y. Zhu;M. Shionyu;Nozomi Ota;Natsumi Shibata;C. Watanabe;Akihito Mizusawa;R. Sasaki;T. Mizukami;Isamu Shiina;M. Hasegawa
中科院分区：
文献类型：
--
作者：
Makoto Tanaka;Y. Zhu;M. Shionyu;Nozomi Ota;Natsumi Shibata;C. Watanabe;Akihito Mizusawa;R. Sasaki;T. Mizukami;Isamu Shiina;M. Hasegawa
日黛芬-F（RID-F）对20 S蛋白酶体的蛋白水解活性有较强的抑制作用，但对26 S蛋白酶体的抑制作用较差。在这里，我们报告了几种缀合物的制备，其中各种肽连接到RID-F。与肽组成的7个氨基酸残基的共轭物显着抑制26 S蛋白酶体。特别地，与八精氨酸肽（R8，所谓的细胞穿透肽）缀合的RID-F抑制细胞内蛋白酶体活性并诱导耐药KMS-11骨髓瘤细胞中的细胞死亡。RID-F结合到疏水肽也抑制26 S蛋白酶体，但未能诱导细胞死亡，表明渗透到细胞差。我们推断R8肽具有双重功能：（1）缀合物快速渗透到细胞中增加细胞内药物浓度，足以显示其作用，以及（2）26 S蛋白酶体对缀合物的识别刺激药物进入催化室。在ATPγS存在下，含有R8的RID-F缀合物比在ATP存在下更有效地抑制26 S蛋白酶体，表明药物以与底物类似的方式有效进入催化室。结合RID-F结合物与蛋白酶体活性位点相互作用的对接模拟，R8肽的第二个功能是合理的。因此，缀合的非肽类蛋白酶体抑制剂的细胞穿透肽可以代表一个可行的策略，克服肿瘤细胞的耐药性。
Ridaifen-F (RID-F) potently inhibits proteolytic activities of the 20S proteasome but poorly inhibits those of the 26S proteasome. Here, we report preparation of several conjugates in which various peptides are connected to RID-F. Conjugates with peptides consisting of seven amino acid residues significantly inhibited the 26S proteasome. Particularly, RID-F conjugated to an octaarginine peptide (R8, a so-called cell-penetrating peptide) inhibited intracellular proteasome activities and induced cell death in drug-resistant KMS-11 myeloma cells. RID-F conjugated to hydrophobic peptides also inhibited the 26S proteasome but failed to induce cell death, suggesting poor penetration into cells. We infer that the R8peptide has dual functions: (1) rapid penetration of conjugates into the cell increases intracellular drug concentrations sufficient for exhibition of its effect, and (2) recognition of the conjugates by the 26S proteasome stimulates drug entry into the catalytic chamber. In the presence of ATPγS, RID-F conjugates containing R8inhibited the 26S proteasome more potently than in the presence of ATP, suggesting efficient entry of drugs into the catalytic chamber in a similar fashion to the substrate. Taken together with docking simulations of RID-F conjugate interactions with proteasome active sites, the second function of R8peptide is plausible. Thus, the conjugation of nonpeptidic proteasome inhibitors to a cell-penetrating peptide could represent a viable strategy for overcoming the drug-resistance of tumor cells.