Development of cyclic peptomer inhibitors targeting the polo-box domain of polo-like kinase 1

被引：45

作者：

Murugan, Ravichandran N. ^{[1
]}

Park, Jung-Eun ^{[2
]}

Lim, Dan ^{[3
]}

Ahn, Mija ^{[1
]}

Cheong, Chaejoon ^{[1
]}

Kwon, Taeho ^{[2
,4
,5
,6
]}

Nam, Ky-Youb ^{[7
]}

Choi, Sun Ho ^{[2
,8
]}

Kim, Bo Yeon ^{[6
]}

Yoon, Do-Young ^{[5
]}

Yaffe, Michael B. ^{[3
]}

Yu, Dae-Yeul ^{[4
]}

Lee, Kyung S. ^{[2
]}

Bang, Jeong Kyu ^{[1
]}

机构：

[1] Korea Basic Sci Inst, Div Magnet Resonance, Chung Buk 363883, Cheongwon, South Korea

[2] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[3] MIT, Dept Biol & Biol Engn, Ctr Canc Res, Cambridge, MA 02139 USA

[4] Korea Res Inst Biosci & Biotechnol, Aging Res Ctr, Taejon 305806, South Korea

[5] Konkuk Univ, Dept Biosci & Biotechnol, Bio Mol Informat Ctr, Seoul 143701, South Korea

[6] Korea Res Inst Biosci & Biotechnol, World Class Inst, Ochang, South Korea

[7] Bioinformat & Mol Design Res Ctr, Seoul 120749, South Korea

[8] Dong A Pharmaceut Co Ltd, Res Labs, Yongin 449905, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 09期

基金：

新加坡国家研究基金会;

关键词：

Polo-box domain (PBD); Cyclic peptomers; Kinase inhibitors; Solid phase peptide synthesis; SMALL-MOLECULE INHIBITORS; PEPTOIDS; ALKYLATION;

D O I：

10.1016/j.bmc.2013.02.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The polo-box domain (PBD) of polo-like kinase 1 (Plk1) is essentially required for the function of Plk1 in cell proliferation. The availability of the phosphopeptide-binding pocket on PBD provides a unique opportunity to develop novel protein-protein interaction inhibitors. Recent identification of a minimal 5-residue-long phosphopeptide, PLHSpT, as a Plk1 PBD-specific ligand has led to the development of several peptide-based inhibitors, but none of them is cyclic peptide. Through the combination of single-peptoid mimics and thio-ether bridged cyclization, we successfully demonstrated for the first time two cyclic peptomers, PL-116 and PL-120, dramatically improved the binding affinity without losing mono-specificity against Plk1 PBD in comparison with the linear parental peptide, PLHSpT. These cyclic peptomers could serve as promising templates for future drug designs to inhibit Plk1 PBD. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2623 / 2634

页数：12

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