Design,Synthesis And Activity Of Peptide Inhibitors Targeted At PLK1

Objective: Polo-like kinases(PLKs)are a class of serine/threonine protein kinases with highly conserved structure and function,which can participate in the regulation of different stages of cell cycle.There are four subtypes of PLKs(PLK1,PLK2,PLK3 and PLK4),which have similar structures.Their N-terminal is the highly conserved ATP domain,and their C-terminal is the PBD(polo-box domain)characterized by catalytic activity and subcellular dynamic localization.The over expression of PLK1 in the four subtypes can lead to the occurrence of multiple cancers,PLK1 has become an important target for the development of anti-tumor drugs.In this paper,the endogenous peptide fragment PLHSp T bound to PBD of PLK1 subunit was used as the lead compound for structural modification.The aim is to improve the metabolic stability and bioavailability of peptide compounds,and to obtain peptide inhibitors with high selectivity and strong binding ability.Method: According to the crystal complex binding mode of PLHSp T and PBD,the N-terminal(P5 segment)of pentapeptide fragment was restructured,and the proline of P5 segment was replaced by non-natural amino acid or proline analogue,and the target compound was synthesized by solid phase polypeptide synthesis.The inhibition of PLK1 activity was determined by in vitro enzyme level assay.Results: Nine compounds were synthesized and characterized by NMR and MS.The activity of the enzyme was tested.The inhibitory effect of compound ZT-8(87.1%)was higher than that of the positive control ZT-2(85.9%).