Design, synthesis and evaluation of D-amino acid-containing peptidomimetics targeting the polo-box domain of polo-like kinase 1
Design, synthesis and evaluation of D-amino acid-containing peptidomimetics targeting the polo-box domain of polo-like kinase 1
复制标题
针对 polo 样激酶 1 的 polo-box 结构域的含 D-氨基酸的肽模拟物的设计、合成和评估
DOI：
10.1016/j.bioorg.2019.02.022
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发表时间：
2019
影响因子：
5.1
通讯作者：
Jiang Cheng
中科院分区：
文献类型：
--
作者：
Li Zhiyan;Zhang Zhenguo;Chen Yanhong;Tang Shijun;Lin Tongyuan;Huang Jingfang;Li Bo;Jiang Cheng
以已报道的Polo-like kinase1(Plk1)Polo-box结构域(PBD)抑制剂为基础，设计并合成了一系列含有d-氨基酸的多肽类化合物。用我们的荧光偏振(FP)法评价了它们对Plk1、Plk2和Plk3 PBD的抑制活性。化合物18与PLK1PBD结合，IC50值为0.80 μM，在100 μM时对PLK2PBD或Plk3PBD几乎没有抑制作用。化合物18通过剂量依赖的方式减少新合成的蛋白质，使G2/M期细胞比例增加，从而诱导Hela细胞发生凋亡。与L-肽抑制剂LHSPTA相比，化合物18在大鼠血浆中表现出更好的稳定性。这些新型氨基酸修饰的选择性Plk1 PBD抑制剂可能为进一步优化提供新的先导化合物。
A series ofd-amino acid-containing peptidomimetics were designed, synthesized as novel polo-like kinase 1 (Plk1) polo-box domain (PBD) inhibitors based on the reported peptide Plk1 PBD inhibitor. Their inhibitory activity to Plk1, Plk2, and Plk3 PBD were evaluated using our fluorescence polarization (FP) assay. Compound18bound to Plk1 PBD with IC50of 0.80 μM and showed nearly no inhibition to Plk2 PBD or Plk3 PBD at 100 μM. Compound18induced Hela cells to undergo apoptosis by increasing the ratio of the cells at the G2/M phase by decreasing the neosynthesized proteins in a dose-dependent manner from 50 to 150 μM. Compound18showed improved stability in rat plasma compared tol-peptide inhibitor LHSpTA. These noveld-amino acid modified selective Plk1 PBD inhibitors may provide new lead compounds for further optimization.