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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

李芝艳, 刘婕, 李冰艳, 江程

李芝艳, 刘婕, 李冰艳, 江程. 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[J]. 中国药科大学学报, 2020, 51(3): 287-294. DOI: 10.11665/j.issn.1000-5048.20200305
引用本文: 李芝艳, 刘婕, 李冰艳, 江程. 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[J]. 中国药科大学学报, 2020, 51(3): 287-294. DOI: 10.11665/j.issn.1000-5048.20200305
LI Zhiyan, LIU Jie, LI Bingyan, JIANG Cheng. Design, synthesis and evaluation of peptidomimetics targeting the polo-box domain of polo-like kinase 1[J]. Journal of China Pharmaceutical University, 2020, 51(3): 287-294. DOI: 10.11665/j.issn.1000-5048.20200305
Citation: LI Zhiyan, LIU Jie, LI Bingyan, JIANG Cheng. Design, synthesis and evaluation of peptidomimetics targeting the polo-box domain of polo-like kinase 1[J]. Journal of China Pharmaceutical University, 2020, 51(3): 287-294. DOI: 10.11665/j.issn.1000-5048.20200305

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

基金项目: 国家自然科学基金资助项目(No.81573278); 2017年江苏省高等学校优秀科技创新团队资助项目

Design, synthesis and evaluation of peptidomimetics targeting the polo-box domain of polo-like kinase 1

Funds: This work has been financially supported by National Natural Science Foundation of China (No. 81573278) and the Excellent Science and Technology Innovation Team Projects of Jiangsu Provincal Universities in 2017
  • 摘要: 为寻找新型的作用于polo-box结构域的拟肽类polo样激酶1(Plk1 PBD)抑制剂,将先导化合物(PLHSpT)结构中的磷酸基团替换为羧基,并采用非天然氨基酸进一步改造与优化,设计合成了一系列不含磷酸基团的拟肽类Plk1 PBD抑制剂(化合物7a~7u)。设计合成的21个拟肽类化合物均对Plk1 PBD抑制作用较强,其中化合物7l高选择性地抑制Plk1 PBD,IC50为0.285 μmol/L,体外对HeLa肿瘤细胞株的生长抑制作用优于含磷酸基团的化合物。经过非天然氨基酸修饰和改造,化合物在大鼠血浆中的稳定性得到了提高。实验证明,用羧基替换磷酸基团并进行肽链的结构改造,可以获得成药性更好的选择性Plk1 PBD抑制剂。
    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.
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出版历程
  • 收稿日期:  2020-03-26
  • 修回日期:  2020-05-12
  • 刊出日期:  2020-06-24

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