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化学进展 2016, Vol. 28 Issue (7): 1084-1098 DOI: 10.7536/PC160107 前一篇   后一篇

• 综述与评论 •

β-模拟肽的构象限制在药物设计中的应用

袁硕, 孙德群*   

  1. 山东大学(威海)海洋学院 威海 264209
  • 收稿日期:2016-01-01 修回日期:2016-04-01 出版日期:2016-07-15 发布日期:2016-05-17
  • 通讯作者: 孙德群 E-mail:dequn.sun@sdu.edu.cn
  • 基金资助:
    国家自然科学基金项目（No.21472243）资助
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The Conformational Restriction of β-Peptidomimetics in Drug Design

Yuan Shuo, Sun Dequn*   

  1. Marine College, Shandong University, Weihai, Weihai 264209, China
  • Received:2016-01-01 Revised:2016-04-01 Online:2016-07-15 Published:2016-05-17
  • Supported by:
    The work was supported by the National Natural Science Foundation of China (No.21472243).
传统肽类药物在体内环境下易水解，具有不稳定性，以β-氨基酸为基本单位的β-肽相比传统的α-肽，药代动力学参数更加良好，因此蕴藏更大的药物开发价值。β-氨基酸构象限制后，可发展为β-模拟肽。构象限制的目的是使β-模拟肽链趋向于形成固定的二级结构，按特定方式折叠，最终具备理想的三维空间结构，嵌合于特定的酶和受体，从而提高目标肽的生物活性和代谢稳定性。本文主要综述β-模拟肽局部修饰和肽链整体环化的构象限制方法以及限制后生物活性或物理化学参数的变化，以此为β-肽类药物的设计原则和方法提供指导，减少设计盲目性。
关键词： β-模拟肽, 构象限制, 生物活性, 肽类药物设计
The traditional peptide drugs are unstable in vivo conditions due to hydrolysis. The β-peptide that composed of β-amino acids has improved pharmacokinetic parameters than α-peptide and is valuable in drug development. The conformation restricted β-amino acids can form the β-peptidomimetics in order to improve its biological activity and metabolic stability. The restricted β-peptidomimetics can form fixed secondary structure and fold with specific way, then it has an ideal three-dimensional structure and embed in specific enzymes or receptors eventually. This review describes the methods of conformational restriction and the changes of biological activity or physical and chemical parameters after conformational restriction for β-peptidomimetics. Two kinds of conformationally restricted β-peptidomimetics including the local conformational restriction and the overall cyclization of β-peptidomimetics are reviewed. This paper could provide guidance for the rational design of β-peptide drugs.

Contents
1 Introduction
2 Local conformational restriction of β-peptides
2.1 Monoalkylating β2 or β3-amino acids
2.2 Dialkylating β2,3-amino acids
2.3 Cα-fluorinated β-amino acids
2.4 N-substituted β-amino acids
2.5 Ring substituted β-amino acids
3 The overall cyclization of β-peptides
3.1 Cyclization between the head and tail
3.2 Cyclization between the side chains
4 Research methods of the conformational restriction
4.1 Circular dichroism spectroscopy
4.2 Infrared spectroscopy
4.3 X-ray diffraction analysis
4.4 Nuclear magnetic resonance
4.5 Theoretical calculations
5 Conclusion

Key words: β-peptidomimetics, conformational restriction, biological activity, peptide drug design

中图分类号: 

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