订书肽的合成与活性研究进展  

Research progress in the synthesis and bioactivity of stapled peptide

作　　者：李博 杨潇骁 李莉[1] 

机构地区：[1]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,北京100050

出　　处：《药学学报》2017年第5期685-698,共14页Acta Pharmaceutica Sinica

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)

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。Acting as the key step of various cell signaling pathways, protein-protein interaction （PPIs） plays a significant role in the regulation of biological functions. Many of the proteins involved are potential drug targets, therefore manipulation of PPI would greatly a great interest in physiology and pharmacology. Most PPIs could not be directly targeted by small molecule drugs due to their flat and shallow interaction surfaces. Selective regulator may be obtained by extraction and chemical synthesis helical peptide that forms folding substructure scaffold in PPI. However, most peptides when separated from its protein progenitor are not able to maintain its biological active helical structure, but tend to form random coil conformation, which is vulnerable to enzyme and suffer low potency and drugability. By modification through all-hydrocarbon bridged cyclic peptide designating ＇stapled peptide＇, it turned out to be the most effective and directive methodology to solve the drawbacks. Stapled peptide not only can boost its potency, but also its biostability and cell permeability. These significant advantages make peptide stapling an important way of modification, which may definitely generate more and more peptide drug candidates targeting PPIs in the foreseen future. In this paper, chemistry and bioactivity of the stapled peptides reported up-to-date are systematically reviewed and discussed.

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 

分 类 号：R916[医药卫生—药学]