本文關(guān)鍵詞： 蛋白-蛋白相互作用 α-螺旋肽 多肽藥物 肽結(jié)構(gòu)改造 訂書(shū)肽　出處：《藥學(xué)學(xué)報(bào)》2017年05期 　論文類(lèi)型：期刊論文

【摘要】：蛋白-蛋白相互作用(PPIs)在調(diào)節(jié)機(jī)體生命活動(dòng)中起著決定性的作用,是體內(nèi)眾多信號(hào)傳導(dǎo)通路的關(guān)鍵機(jī)制,其中很多關(guān)鍵蛋白質(zhì)是可以利用的潛在藥物靶點(diǎn)。探索有效調(diào)控蛋白-蛋白相互作用的方法,將對(duì)生理學(xué)以及藥物研究大有裨益。絕大多數(shù)蛋白-蛋白相互作用以相對(duì)較大且較淺的作用面模式進(jìn)行,小分子難以形成有效結(jié)合或調(diào)控。將蛋白-蛋白相互作用中以多肽二級(jí)結(jié)構(gòu)為支撐骨架的折疊亞結(jié)構(gòu)域中的α-螺旋肽單獨(dú)提取出來(lái),通過(guò)化學(xué)合成的方法加以構(gòu)建將有可能得到選擇性作用于靶標(biāo)蛋白的活性多肽藥物先導(dǎo)物。然而大部分多肽片段在離開(kāi)蛋白質(zhì)整體結(jié)構(gòu)后將無(wú)法穩(wěn)定形成結(jié)合所需的二級(jí)結(jié)構(gòu),而易于形成無(wú)規(guī)則卷曲構(gòu)象從而導(dǎo)致結(jié)合活性下降,并且更易受肽酶的降解,無(wú)法直接成藥。應(yīng)用全碳骨架形成側(cè)鏈環(huán)合結(jié)構(gòu)改造多肽來(lái)穩(wěn)定α-螺旋肽的活性構(gòu)象,即訂書(shū)肽(stapled peptide),成為克服這一缺陷的最直接最有效方法。該方法不僅可以提高其原本的蛋白結(jié)合活性,而且具有較高的代謝穩(wěn)定性和細(xì)胞膜通透性�；谶@些顯著的優(yōu)勢(shì),訂書(shū)肽已經(jīng)成為一類(lèi)重要的活性多肽結(jié)構(gòu)改造方式,也必將由此形成更多的以蛋白-蛋白相互作用為靶點(diǎn)的新型多肽藥物。本文將著重綜述并討論通過(guò)化學(xué)手段合成訂書(shū)肽的方法及其藥理活性研究進(jìn)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.

【作者單位】： 中國(guó)醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院藥物研究所北京市活性物質(zhì)發(fā)現(xiàn)與適藥化研究重點(diǎn)實(shí)驗(yàn)室;
【基金】：中國(guó)醫(yī)學(xué)科學(xué)院醫(yī)學(xué)與健康科技創(chuàng)新工程項(xiàng)目(2016-I2M-3-008) 中央公益性科研院所基本科研業(yè)務(wù)費(fèi)項(xiàng)目(2015CX08)
【分類(lèi)號(hào)】：R914.5

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