Design, synthesis and evaluation of peptidomimetics targeting the polo-box domain of polo-like kinase 1
10.11665/j.issn.1000-5048.20200305
- VernacularTitle:作用于polo-box结构域的拟肽类polo样激酶1抑制剂的设计、合成及其生物活性
- Author:
Zhiyan LI
1
;
Jie LIU
;
Bingyan LI
;
Cheng JIANG
Author Information
1. 中国药科大学江苏省药物分子设计与成药性优化重点实验室
- Publication Type:Journal Article
- Keywords:
Plk1 PBD;
inhibitor;
synthesis;
antitumor
- From:
Journal of China Pharmaceutical University
2020;51(3):287-294
- CountryChina
- Language:Chinese
-
Abstract:
To identify novel inhibitors targeting the polo-box domain of polo-like kinase 1 (Plk1 PBD), a series of new peptidomimetics (7a-7u) without phosphate group were designed and synthesized, where the phosphate group in the structure of the selective Plk1 PBD inhibitor PLHSpT was replaced by the carboxyl group, and the unnatural amino acids were applied for further modification and optimization. The 21 peptidomimetic compounds designed and synthesized had a strong inhibitory effect on Plk1 PBD, of which compound 7l highly selectively inhibited Plk1 PBD with IC50 of 0.285 μmol/L. The growth inhibition effect of HeLa tumor cell lines in vitro was better than that of compounds containing phosphate group. Moreover, the stability of the compound in rat plasma was improved by unnatural amino acids. Thus it is proved that selective Plk1 PBD inhibitor with improved characters can be obtained by replacing the phosphate group with a carboxyl group and restructuring the peptide chain.
