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脂肪链在吡咯-咪唑聚酰胺及其结合物与B-DNA键合中的作用

江世坤1, 王普1, 吴艳玲2, 张文1   

  1. 1. 浙江工业大学药学院生物制药系 杭州 310014;
    2. 浙江疾病预防控制中心病毒检测所 杭州 310051
  • 收稿日期:2011-02-01 修回日期:2011-03-01 出版日期:2011-11-24 发布日期:2011-08-30
  • 通讯作者: 王普, 张文 E-mail:wzhang63@zjut.edu.cn; wangpu@zjut.edu.cn
  • 基金资助:

    浙江省钱江人才计划项目(No.2008R10G2020015)、浙江省自然科学基金项目(No.Y2090851) 和卫生部科学研究基金项目(No.WKJ2009-2-019)资助

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The Role of Aliphatic Chains in Pyrrole-Imidazole Polyamides and Their Conjugates Binding to DNA

Jiang Shikun1, Wang Pu1, Wu Yanling2, Zhang Wen1   

  1. 1. Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China;
    2. Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China
  • Received:2011-02-01 Revised:2011-03-01 Online:2011-11-24 Published:2011-08-30
  • Contact: Wang Pu, Zhang Wen E-mail:wzhang63@zjut.edu.cn; wangpu@zjut.edu.cn

吡咯-咪唑聚酰胺是一类人工合成的能够在B-DNA小沟特异性识别碱基序列的有机小分子,并且能通过细胞膜进入细胞,调控基因的表达。它主要由五元杂环化合物N-甲基吡咯(Py)、N-甲基咪唑(Im)、N-甲基-3-羟基吡咯(Hp)芳香氨基酸及脂肪链氨基酸组成。在这种小分子对生物大分子识别事件中, 脂肪链作为构建聚酰胺及其结合物的一部分, 在聚酰胺特异性识别DNA、延长DNA识别序列、连接分子荧光标记、对DNA指定位点的烷基化及基因调控等方面都起着非常重要的作用。本文阐述了脂肪链在上述诸方面应用的研究进展,并简要地分析了存在的问题和应用前景。

关键词： 脂肪链, 吡咯-咪唑聚酰胺, 结合物, B-DNA

The pyrrole-imidazole (Py-Im) polyamides represent the only available class of synthetic small molecules which can be designed to recognize virtually any predetermined B-DNA sequence in minor groove and permeate into nucleus to regulate gene expression in vitro & in vivo due to affinities and specificities, and equal or exceed natural eukaryotic transcriptional regulatory proteins. They are mainly composed of N-methylpyrrole (Py), N-methylimidazole (Im), N-methyl-3-hydroxypyrrole (Hp) amino acids and aliphatic chain compounds including aliphatic amino acids. In these moieties, an aliphatic chain as a part of constructing polyamides and their conjugates plays a very important role in extending and specifically recognizing predetermined DNA sequences, linking functioned bioactive molecules to polyamides, and gene regulation. Understanding the role of aliphatic chains in polyamides and their conjugates may help us to better design suitable polyamides to be applied in DNA recognition,which can speed up research of polyamides as a gene-targeted clinical drug. In this paper, we review the application of aliphatic chains of polyamides and their conjugates in polyamides binding to B-DNA minor groove and analyze existing problems.

Contents
1 Introduction
2 The effect of γ-aminobutyric acid and its structural variants on interaction of polyamides with DNA
2.1 Role of γ-aminobutyric acid in DNA recognition by polyamides
2.2 The effect of structural modification with γ-aminobutyric acid on DNA recognition affinity and specificity by polyamides
2.3 The effect of cyclic polyamides linked by γ-aminobutyric acid on DNA recognition
3 The effect of β-alanine and its structural variants on interaction of polyamides with DNA
3.1 Role of β-alanine in DNA recognition by polyamides
3.2 The influence of β-alanine structural modification on DNA recognition by polyamides
4 Role of aliphatic chains in unusual structural polyamides
5 Role of the linkers of polyamides in biological application
5.1 Role of the linkers in polyamide-fluorophore conjugates
5.2 Role of the linkers in polyamide-alkylating agent conjugates
5.3 Role of the linkers of polyamides in gene regulation
6 Conclusion and outlook

 

Key words: aliphatic chains, Py-Im polyamides, conjugates, B-DNA

中图分类号: 

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