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

LI Zhiyan; LIU Jie; LI Bingyan; JIANG Cheng

doi:10.11665/j.issn.1000-5048.20200305

Journal of China Pharmaceutical University > 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

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

LI Zhiyan^1,2,3,
LIU Jie^1,2,3,
LI Bingyan^1,2,3,
JIANG Cheng^1,2,3

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

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Received Date: March 26, 2020
Revised Date: May 12, 2020

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Abstract

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.
- Plk1 PBD,
- inhibitor,
- synthesis,
- antitumor

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References (22)

References

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