本文選題：多肽藥物 + 肽體　； 參考：《電子科技大學(xué)》2017年碩士論文

【摘要】：多肽在人體代謝的各個(gè)過(guò)程都承擔(dān)了重要作用,其中包括細(xì)胞增殖、細(xì)胞分化、消化代謝、免疫防御、腫瘤病變等。在1953年,美國(guó)生化學(xué)家第一次人工合成了催產(chǎn)素這一多肽,標(biāo)志著多肽可以為人們所利用。在經(jīng)歷了長(zhǎng)期發(fā)展之后,現(xiàn)在在全球范圍內(nèi)上市的多肽藥物已經(jīng)超過(guò)了 80種,并且還有很多多肽藥物處于正在研究的階段。與其它藥物相比,多肽類藥物具有一些獨(dú)特的優(yōu)勢(shì):藥效好,特異性高,通常在人體內(nèi)不會(huì)產(chǎn)生累積,很少和其他藥物發(fā)生交叉作用。多肽藥物雖然具有上述的這些優(yōu)勢(shì),不過(guò)同其它的藥物對(duì)比,多肽藥物同樣存在著缺點(diǎn):多肽的穩(wěn)定性較低,常常被肽酶分解為氨基酸,這導(dǎo)致多肽的半衰期很短,為了保證藥效需要重復(fù)為患者給藥,很不方便。為解決這一問(wèn)題,學(xué)者們探索了很多新方法,蛋白融合技術(shù)是目前延長(zhǎng)蛋白和多肽類藥物半衰期的有效手段之一。Fc融合則是目前研究最多、進(jìn)展最快的蛋白融合技術(shù),它通常是將IgG蛋白的Fc段同篩選出的多肽融合在一起。這樣的多肽(Peptide)-抗體(Antibody)融合蛋白被稱為“肽體”(Peptibody)。研究者發(fā)現(xiàn):在羅米司亭(romiplostim)這一藥物中,Fc段和多肽通過(guò)不同的方式連接所得到的活性差別極大。通過(guò)Fc的C端和多肽連接的活性相比于通過(guò)Fc的N端同多肽連接要高出10倍以上。但對(duì)多肽與抗體連接方式與藥效間的關(guān)系和相應(yīng)的機(jī)制還尚不清楚,對(duì)其的研究也更多集中在實(shí)驗(yàn)方面,理論上的探索寥寥無(wú)幾。本學(xué)位論文擬從結(jié)構(gòu)生物信息學(xué)角度出發(fā),利用ITASSER在線服務(wù)預(yù)測(cè)蛋白結(jié)構(gòu)以及ZDOCK對(duì)接蛋白從而構(gòu)建相關(guān)的模型,預(yù)測(cè)分析出不同連接方式的肽體同受體的結(jié)合情況。然后通過(guò)AMBER等分子動(dòng)力學(xué)模擬軟件計(jì)算結(jié)合自由能以及能量分解的方法研究不同結(jié)合方式的肽體同受體的相互作用,從理論上嘗試解釋不同肽體藥物連接方式不同所致的活性不同提供理論支持。也為以后設(shè)計(jì)肽體藥物給出理論上的預(yù)測(cè)。
[Abstract]:Polypeptides play an important role in various processes of human metabolism, including cell proliferation, cell differentiation, digestion and metabolism, immune defense, tumor lesions, and so on. In 1953, American biochemists synthesized oxytocin for the first time, indicating that it could be used. After a long period of development, there are more than 80 polypeptide drugs on the market worldwide, and many polypeptide drugs are still in the research stage. Compared with other drugs, polypeptide drugs have some unique advantages: good efficacy, high specificity, usually do not accumulate in the human body, and rarely cross with other drugs. Although polypeptide drugs have these advantages, compared with other drugs, polypeptide drugs have the same disadvantages: the stability of peptides is low and they are often decomposed into amino acids by peptidases, which results in short half-lives of peptides. In order to ensure the efficacy of drugs need to be repeated for patients, very inconvenient. In order to solve this problem, many new methods have been explored. Protein fusion technology is one of the effective means to prolong the half-life of protein and polypeptide drugs. FC fusion is the most studied and the most advanced protein fusion technology. It usually fuses FC of IgG protein with selected peptides. This (Antibody) fusion protein is known as the Peptide body. The researchers found that in romistin (romiplostim), the activity of the FC segment and the peptide is significantly different from the way in which the peptide is connected. The binding activity of the C terminal of FC to the peptide was 10 times higher than that of the N terminal of FC. However, the relationship between peptide and antibody binding mode and pharmacokinetic activity and the corresponding mechanism are still unclear. The research on peptide and antibody is more focused on the experiment, and the theoretical research is very few. From the point of view of structural bioinformatics, this dissertation intends to use ITASSER online service to predict protein structure and ZDOCK docking protein to construct relevant models, and to predict and analyze the binding of peptide bodies with different binding modes to receptors. Then the binding free energy and energy decomposition were calculated by molecular dynamics simulation software, such as Amber, to study the interaction between peptide and receptor in different binding modes. This paper tries to explain the different activities caused by different peptide drug binding modes theoretically to provide theoretical support. It also provides a theoretical prediction for the design of peptide drugs in the future.
【學(xué)位授予單位】：電子科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R91

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本文編號(hào)：2070433