Division of Magnetic Resonance, Korea Basic Science Institute , 804-1, Yangcheong Ri, Ochang, Chungbuk, Cheongwon 363-883, Republic of Korea.
J Med Chem. 2015 Jan 8;58(1):294-304. doi: 10.1021/jm501147g. Epub 2014 Nov 5.
Recent progress in the development of peptide-derived Polo-like kinase (Plk1) polo-box domain (PBD) inhibitors has led to the synthesis of multiple peptide ligands with high binding affinity and selectivity. However, few systematic analyses have been conducted to identify key Plk1 residues and characterize their interactions with potent Plk1 peptide inhibitors. We performed systematic deletion analysis using the most potent 4j peptide and studied N-terminal capping of the minimal peptide with diverse organic moieties, leading to the identification of the peptidomimetic 8 (AB-103) series with high binding affinity and selectivity. To evaluate the bioavailability of short peptidomimetic ligands, PEGylated 8 series were synthesized and incubated with HeLa cells to test for cellular uptake, antiproliferative activity, and Plk1 kinase inhibition. Finally, crystallographic studies of the Plk1 PBD in complex with peptidomimetics 8 and 22 (AB-103-5) revealed the presence of two hydrogen bond interactions responsible for their high binding affinity and selectivity.
近年来，肽衍生的 Polo 样激酶 (Plk1) Polo 框结构域 (PBD) 抑制剂的研究取得了进展，合成了具有高结合亲和力和选择性的多种肽配体。然而，很少有系统的分析来确定关键的 Plk1 残基，并描述它们与强效 Plk1 肽抑制剂的相互作用。我们使用最有效的 4j 肽进行了系统的缺失分析，并研究了最小肽的 N 端加帽与各种有机基团的相互作用，从而确定了具有高结合亲和力和选择性的拟肽 8（AB-103）系列。为了评估短肽模拟物配体的生物利用度，合成了聚乙二醇化的 8 系列，并与 HeLa 细胞孵育，以测试细胞摄取、抗增殖活性和 Plk1 激酶抑制作用。最后，通过晶体学研究 Plk1 PBD 与拟肽 8 和 22（AB-103-5）的复合物，揭示了两个氢键相互作用的存在，这是它们具有高结合亲和力和选择性的原因。
