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研究生:陳彥儒
研究生(外文):Yan Ru Chen
論文名稱:抗流行性感冒病毒藥物抑制作用的機制探討
論文名稱(外文):The Inhibitory Mechanisms of Anti-influenza Virus Drugs in Cell-based Studies
指導教授:洪錦堂洪錦堂引用關係
指導教授(外文):J. T. Horng
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:91
中文關鍵詞:流行性感冒病毒抗病毒藥物
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流行性感冒病毒是重要的致病原,每年在世界各地均造成重大的公共衛生威脅,近期由於高致病性的禽流感H5N1與新型流感H1N1的肆虐,更加深各國對流感病毒的重視,目前臨床上對流感病毒的治療主要仰賴M2離子通道蛋白抑制劑(adamantanes)與neuraminidase抑制劑(zanamivir and oseltamivir),然而,這兩類抗病毒藥物在動物實驗或臨床應用都已經有抗藥性病毒株的報導出現。透過與國家衛生研究院的合作,我們利用MDCK細胞株對篩選出來的抗流感化合物CSV0C019002進行抗病毒機轉的研究,以不同的流感病毒株測試後,觀察到CSV0C019002對流感病毒的抑制作用並非僅侷限在特定的病毒株。我們發現CSV0C019002成功的保護細胞免於遭受病毒誘發的細胞病變,雖然當移除培養基中的化合物後,保護的效果便消失了。以時程試驗分析,CSV0C019002對於病毒早期進入細胞的過程並沒有很強的抑制效果,同時,該化合物對病毒的保護作用需要透過長期的藥物處理。更進一步探討分子層級的抗病毒機轉,CSV0C019002顯著的抑制病毒蛋白與病毒核酸的合成。而細胞凋亡的標記caspase 3和PARP的活化也受該化合物的抑制。最後,在螢光顯微鏡的觀察下,我們發現CSV0C019002處理情況下,病毒的M1蛋白明顯的被侷限在細胞核中。因此,在我們的研究中發現,細胞模式下,CSV0C019002是極具發展潛力的抗病毒藥物,更進一步的動物實驗有助於我們了解CSV0C019002在活體中的抗病毒活性。
Influenza A viruses are medically important viral pathogens that cause significant mortality and morbidity throughout the world. The recent emergence of highly pathogenic influenza A virus (H5N1) and novel influenza A virus (H1N1) pose a serious health threat. Current antivirals against the M2 ion channel (adamantanes) and the neuraminidase (zanamivir and oseltamivir) were clinical available. However, both seasonal and H5N1 influenza A viruses have developed resistance to these two types of drugs. Here, we show that the anti-influenza virus compound, CSV0C019002 (collaboration from NHRI) was effective against a spectrum of influenza A and B viruses in MDCK cell line (IC50: 4.27μM). CSV0C019002 blocked cytopathic effect induced by viral infection, although the protection was diminished after depriving of this compound in the medium. Through time-of-addition assay, we found that CSV0C019002 didn’t act on the early entry stage; moreover, the antiviral activity only existed in long-term treatment. Further investigation of its molecular mechanism, CSV0C019002 was demonstrated to reduce both viral protein and RNA synthesis. Strikingly, apoptosis markers, caspase 3 and PARP cleavage were also inhibited by CSV0C019002 treatment. In immunofluorescence microscopy, viral matrix protein (M1) was accumulated in cellular nucleus by CSV0C019002. In summary, we demonstrate that CSV0C019002 is a potent anti-influenza virus compound in the cell-based assay. Additional animal model test is in progress.
指導教授推薦書 --------------------------------------------口試委員會審定書 ------------------------------------------授權書 ----------------------------------------------------誌謝 ---------------------------------------------------- iv英文摘要 ------------------------------------------------- v中文摘要 ------------------------------------------------ vi目錄 ---------------------------------------------------viii圖表目錄 ------------------------------------------------ ix第一章 緒論 ---------------------------------------------- 1第二章 研究目的 ----------------------------------------- 10第三章 實驗材料與方法 ----------------------------------- 12第四章 研究結果 ----------------------------------------- 21第五章 總結與討論 --------------------------------------- 26参考文獻 ------------------------------------------------ 38圖表 ---------------------------------------------------- 53
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