β-模拟肽的构象限制在药物设计中的应用

摘要

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0α-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.%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.