订书肽的合成与活性研究进展

发布时间：2018-02-17 05:55

本文关键词： 蛋白-蛋白相互作用 α-螺旋肽多肽药物肽结构改造订书肽　出处：《药学学报》2017年05期 　论文类型：期刊论文

【摘要】：蛋白-蛋白相互作用(PPIs)在调节机体生命活动中起着决定性的作用,是体内众多信号传导通路的关键机制,其中很多关键蛋白质是可以利用的潜在药物靶点。探索有效调控蛋白-蛋白相互作用的方法,将对生理学以及药物研究大有裨益。绝大多数蛋白-蛋白相互作用以相对较大且较浅的作用面模式进行,小分子难以形成有效结合或调控。将蛋白-蛋白相互作用中以多肽二级结构为支撑骨架的折叠亚结构域中的α-螺旋肽单独提取出来,通过化学合成的方法加以构建将有可能得到选择性作用于靶标蛋白的活性多肽药物先导物。然而大部分多肽片段在离开蛋白质整体结构后将无法稳定形成结合所需的二级结构,而易于形成无规则卷曲构象从而导致结合活性下降,并且更易受肽酶的降解,无法直接成药。应用全碳骨架形成侧链环合结构改造多肽来稳定α-螺旋肽的活性构象,即订书肽(stapled peptide),成为克服这一缺陷的最直接最有效方法。该方法不仅可以提高其原本的蛋白结合活性,而且具有较高的代谢稳定性和细胞膜通透性。基于这些显著的优势,订书肽已经成为一类重要的活性多肽结构改造方式,也必将由此形成更多的以蛋白-蛋白相互作用为靶点的新型多肽药物。本文将着重综述并讨论通过化学手段合成订书肽的方法及其药理活性研究进展。
[Abstract]:Protein protein interaction (PPIs) plays a crucial role in regulating life activities, is a key mechanism in many signal transduction pathways, many of the key proteins as potential drug targets can be used. To effectively control the protein-protein interactions, the physiology and drug research be of great advantage. The vast majority of protein protein interactions in a relatively large and shallow surface model, it is difficult to form an effective combination of small molecules or regulation. Protein protein interactions with peptide two level structure for folding sub domain supporting skeleton of the alpha helical peptide isextracted to construct active polypeptide drug precursor there will probably be a selective effect on target proteins by chemical synthesis method. However, most of peptide fragments in protein structure will not be able to leave the overall stability A combination of two level structure required, and is easy to form a random coil conformation resulting in decreased binding activity, degradation and more susceptible to peptidase, not directly medicine. Application of carbon skeleton formation of side chain structure transformation of the active conformation of helical peptide peptide cyclization to stable alpha, namely peptide (stapled peptide) book book and become the most direct and effective method to overcome this defect. This method can not only improve the binding activity of the protein, metabolic stability and membrane permeability and high. These advantages based on the book of peptides have become an important class of bioactive peptide structure transformation way, will thus form more protein protein interaction model for peptide drug targets. This paper will focus on the review and discussion by means of chemical synthesis and pharmacological activity of the peptide stapling progress.

【作者单位】：中国医学科学院北京协和医学院药物研究所北京市活性物质发现与适药化研究重点实验室;
【基金】：中国医学科学院医学与健康科技创新工程项目(2016-I2M-3-008) 中央公益性科研院所基本科研业务费项目(2015CX08)
【分类号】：R914.5

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