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標題: | 以抑制核蛋白三聚體之生成設計及合成抗流感藥物 Design and Synthesis of Anti-influenza Drugs by Inhibiting the Formation of Nucleoprotein Trimer |
作者: | Yi-Chou Huang 黃乙洲 |
指導教授: | 方俊民(Jim-Min Fang) |
關鍵字: | 抗流感藥物,核蛋白, Anti-influenza Drugs,Nucleoprotein, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 摘要
流行性感冒病毒造成每年的流行病,有時甚至造成更嚴重的全球性流行病。全球每年因流行性感冒而死亡的人數高達250,000至500,000人。 甲型流感病毒會根據神經胺酸酶 (NA) 和血液凝集素 (HA) 以不同亞型進行表現。抗流感藥物,如克流感及瑞樂沙是作為神經胺酸酶 (NA) 的抑制劑。在宿主細胞核中形成核糖核蛋白複合物 (RNPs) 是造成甲型流感病毒致病的主要原因之一。核糖核蛋白複合物由RNA聚合酶、RNA片段及核蛋白 (NP) 所構成。由於核蛋白在不同亞型的流感病毒中較為恆定,故我們將NP–NP作用力作為發展新型流感藥物的目標。 E339A...R416A鹽橋作用力是核蛋白單體間不可或缺的作用力。先前,由一個中央研究院的研究團隊利用高通量藥物篩選系統從資料庫中篩選出一些小分子化合物作為前導化合物。以化合物A的結構為基礎,我們設計並合成一些小分子去破壞鹽橋以及其他作用力,包含氫鍵、疏水和π–π堆疊等作用力,進而提升對於流感病毒的抑制效果。此外,為了確認核蛋白單體間實際的鍵結位置,我們合成了一些芳基疊氮衍生物用於進行光親合標記實驗。 在本篇研究中,我們首先在化合物A的嗎啉基團置換成1,1-二苯甲胺基團,合成出化合物13a以及13b。另外,我們也合成出芐胺衍生物22a和22b。我們也進一步合成出4-疊氮芐胺基衍生物30、1-苯-1-(4-疊氮苯)甲胺基衍生物36以及1,1-雙(4-疊氮苯)甲胺基衍生物42用於光親合標記實驗。在生物活性檢測結果中指出,化合物13a具有和化合物A相近的抗流感活性。疊氮化合物36以及42也具有好的抗流感活性,並作為有潛力的光親合標記探針。然而,化合物22a和30顯示出較低的抗流感活性,並且化合物13b及22b也因疏水性過高而無法進行生物活性檢測。 Abstract Influenza viruses cause yearly epidemics and occasionally more severe pandemics, which lead to high fatality The worldwide death toll of influenza epidemics is in the range of 250,000 to 500,000 each year. Influenza A virus is characterized as different subtypes according to neuraminidase (NA) and hemagglutinin (HA). The anti-influenza drugs Tamiflu and Relenza act as NA inhibitors. Formation of ribonucleoprotein complexes (RNPs) in the nucleus of the host cell is one of the main causes of influenza A virus pathogenesis. RNPs are composed of RNA polymerase, RNA fragment and nucleoprotein (NP). Because NP is substantially more conserved, we chose to develop the anti-influenza drugs by disrupting the NP–NP interaction. E339A...R416A salt bridge interaction between NP monomers is essential. A research team in Academia Sinica has previously conducted a high-throughput screening of the chemical library to identify some small molecules as anti-influenza agents by disrupting the NP–NP interaction. Based on the structure of compound A, we thus designed and synthesized small molecules that may disrupt the salt bridge interaction, and further impose on other interactions, including hydrogen bonding, hydrophobic interaction and π–π stacking interaction, to increase their inhibitory activities against influenza viruses. To verify the binding sites between NP monomers, we further synthesized the aryl azide derivatives for photoaffinity labeling experiments. In this study, we first synthesized (1,1-diphenylmethyl)amino derivatives 13a and 13b replacing the morpholine group in the compound A. The benzylamino derivatives 22a and 22b were also synthesized. We further synthesized the 4-azidobenzylamino derivative 30, 1-phenyl-1-(4-azidophenyl)methylamino derivative 36 and 1,1-bis(4-azidophenyl)methylamino derivative 42 for photoaffinity labeling experiments. The MTS bioassay indicated that compound 13a had anti-influenza activity similar to compound A. The azido compounds 36 and 42 had good anti-influenza activity to serve as potential photoaffinity labeling probes. Nevertheless, the compounds 22a and 30 showed lower anti-influenza activity, and compound 13b and 22b were too hydrophobic to do bioassay. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7686 |
DOI: | 10.6342/NTU201702777 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 化學系 |
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