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研究生:吳冠瑩
研究生(外文):Kuan-Yin Wu
論文名稱:篩選並鑑定抑制腸病毒71型初始轉譯之藥物
論文名稱(外文):Screening and Characterization of Anti-enterovirus 71 Compounds that target viral translation initiation
指導教授:龔思豪
指導教授(外文):Szu-Hao Kung
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術暨檢驗學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:71
中文關鍵詞:抑制腸病毒71型藥物
外文關鍵詞:enterovirus 71 compounds
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腸病毒71型(Enterovirus;EV71)屬於微小RNA病毒科,腸病毒屬。腸病毒71型通常感染年紀較小的孩童,會造成手足口症,重者會產生嚴重的神經疾病。然而,在臨床上並沒有抗腸病毒的藥物能夠使用。 根據以往的研究, 從 LOPAC化合藥物庫篩選出Idarubicin (IDR) 其屬於蒽環黴素類(anthracycline)的化合物能藉由選擇性的抑制腸病毒初始轉譯進而去抑制腸病毒的活性,腸病毒的轉譯作用是利用 病毒 RNA 中 5’未轉譯區的內部核醣體進入區(IRES)來進行,而在轉譯過程中需要一些特定細胞因子稱為 IRES trans-acting factors (iTAFs)的調控。Anthracycline化合物的特性是能夠崁入正在複製中的DNA,所以我們假設IDR能有選擇性的結合在腸病毒IRES RNA來抑制其活性。藉由螢光減弱試驗,我們證明了IDR對EV71, Echovirus 9 and Coxsackievirus A16的IRES RNA有很強的結合能力,但是細胞內的p53 IRES RNA卻不然。我們利用三個不同片段的EV71 IRES (domain I~V, IV, IV~linker),去做更進一步的探討IDR對於EV71 IRES RNA是專一性還是多重性的結合,實驗結果顯示IDR與三個不同的片段EV71 IRES RNA有很強的結合能力,更代表了 IDR是多重性的結合於 EV71 IRES RNA。接下來利用pull-down assay 證明了IDR的確能夠干擾EV71 IRES RNA 與iTAFs (hnRNPA1)的結合,並且有隨著IDR濃度的增加而遞減的趨勢。已有文獻表示,hnRNPA1能與EV71 IRES RNA的domain II, VI所結合,因此也證實了IDR確實能干擾 hnRNPA1與EV71 IRES RNA domain I~V和 domain IV~VI的結合能力, 但是卻不結合於domain IV。根據以上實驗證明了IDR能夠藉由選擇性的結合於EV71 IRES RNA的多重位置進而去干擾其iTAFs的結合能力來抑制腸病毒活性。因為腸病毒IRES RNA擁有多樣性的二級結構 RNA,IDR辨認腸病毒的特殊二級結構RNA而不是辨認特定序列,這些發現與之前的分離抗藥性腸病毒的研究一致。
另外,我們也探討了新一代的蒽環黴素類藥物, Aclarubicin(ACL), Pirarubicin(PIR), Valrubicin(VAL)的抗腸病毒能力,發現ACL抑制腸病毒蛋白合成和病毒感染率較其他兩個類似物強。但是發現ACL對細胞的毒殺能力比IDR來的強(CC50: 107.9μM) than IDR (CC50: 192.1μM).
最後,透過anthracycline分子機制的實驗中,IDR能夠選擇性的抑制腸病毒IRES RNA的活性,藉由蒽環黴素類藥物能指向未來發展出一個廣效性的抗腸病毒藥物。

Human Enterovirus 71 (EV71), a member of genus enterovirus of the family Picornaviridae, commonly causes Hand, Food and Mouth Disease and occasionally neurological complications in young children. To date, there is no specific antiviral agent known to be effective in clinically treating EV71 infections. Previous studies from a drug screen identified an anthracycline compound idarubicin (IDR) that showed anti-EV71 activities by selectively targeting the viral translation initiation. The translation initiation of the enterovirus occurs via the highly structured internal ribosomal entry site (IRES) located at the 5’ untranslated region (5’UTR) of the virus RNA genome, and it is regulated by certain cellular factors called IRES trans-acting factors (ITAFs). As anthracycline compounds are known as DNA intercalators, we hypothesized that IDR may inhibit the viral IRES activity by preferentially binding with the viral IRES RNA. By the fluorescence quenching assay, we showed that IDR binds strongly with viral IRESs from EV71, echovirus 9 and coxsackievirus A16 but only weakly with cellular p53 IRES. To investigate whether IDR exhibited a specific binding or multiple bindings with the viral IRES RNA, three EV71 IRES subfragments covering domain I-V, IV and IV-linker were generated. All these EV71 IRES subfragments displayed strong binding affinities with IDR, indicating that IDR bind at multiple sites within the viral IRES RNA. Moreover, pull-down assay revealed that IDR intervened binding between EV71 IRES RNA and heterogenous nuclear ribonucleoprotein A1 (hnRNPA1), a representative ITAF, in a dose-dependent manner. The hnRNPA1 is known to bind the domains II and VI of the EV71 IRES RNA. We further showed that IDR intervened with the hnRNPA1 bindings with the IRES subfragments containing the domains I-V, and IV-linker, but not the domain IV. These data support a working model that IDR may exhibit an inhibitory effect on enterovirus IRES activity by selectively binding to enteroviral IRES at multiple sites, thereby blocking the binding of ITAFs and the consequent IRES activity. Moreover, because of the secondary structure conservation yet sequence diversity among the enteroviral IRESs, IDR likely acts in a structure-dependent rather than a sequence-dependent manner. These findings are consistent with the previous failure to isolate drug-resistant virus.
To find other anthracycline compounds with anti-EV71 activity, Aclarubicin (ACL), Pirarubicin (PIR), and Valrubicin (VAL) have been evaluated. The results showed that ACL displayed stronger EV71 inhibition in viral protein synthesis and infection rates among the anthracyclines tested. However, ACL showed higher cytotoxicity (CC50: 107.9μM) than IDR (CC50: 192.1μM).
In sum, we have come with a molecular mechanism that elaborates the IDR action in selective inhibition of enterovirus IRES activity. The finding may point to development of a broad-spectrum anti-EV drug based on the anthracycline analogs.

目錄
中文摘要 i
Abstract iii
目錄 v
圖目錄 viii
第一章 緒論 1
第一節 腸病毒71型概述 1
ㄧ、腸病毒分類及特性 1
二、腸病毒顆粒 2
三、腸病毒基因體結構 2
四、腸病毒的生長週期 3
五、腸病毒71型的發現與流行 4
六、腸病毒71型的臨床症狀 5
七、抗病毒藥物發展 5
I. 抑制病毒外殼蛋白 7
II. 抑制病毒蛋白酶(2A, 3C 蛋白酶) 7
III.抑制病毒RNA複製 8
V. 干擾素(interferon, IFN)治療 9
第二節 抗 EV71 藥物的篩選 11
第三節 病毒內部核醣體進入區 12
ㄧ、真核細胞轉譯的起始 12
二、腸病毒轉譯的起始 12
三、腸病毒IRES的結構 13
四、IRES Transacting Factors (ITAFs) 14
第四節 核醣核酸與蛋白質結合研究方法 16
第五節 新 Anthracyclines 藥物介紹 17
第六節 研究動機與方向 18
第二章 實驗材料與方法 19
第一節 實驗材料 19
一、細胞與病毒 (Cell lines and Virus): 19
二、藥品和試劑 (Drugs and Reagent): 19
三、試劑套組與酵素 (Kit and Enzyme): 21
四、引子 (Primer): 22
五、質體 (Plasmids): 22
六、抗體和染劑 (Antibodies and Dye): 23
七、溶液 (Solution): 23
第二節 實驗方法 27
一、細胞株的培養與操作 27
二、病毒培養與定量 28
三、質體建構 29
四、細胞存活率試驗(MTT Assay) 33
五、免疫螢光染色(IFA) 33
六、西方墨點法(Western Blot) 34
七、雙冷光報導RNA製備 36
八、RNA 轉染 (RNA Transfection) 37
九、雙冷光報導基因偵測 (Dual luciferase reporter assay) 38
十、IRES RNA 製備 38
十ㄧ、螢光減弱試驗(Fluorescence Quenching Assay) 39
十二、Pull-down Assay 39
第三章 實驗結果 41
ㄧ、IDR對腸病毒IRES選性的高親和力 41
二、IDR能多重性的結合在不同功能區域的腸病毒IRES 41
三、IDR干擾 hnRNPA1(iTAFs)與腸病毒功能區域的結合 42
四、IDR干擾 hnRNPA1(iTAFs)與腸病毒sub-domains的結合 42
五、新 Anthracyclines 藥物抑制效果與劑量 42
六、新 Anthracycline 藥物濃度的細胞毒性 43
七、新 Anthracycline 藥物能夠抑制EV71蛋白質的產生 43
八、新 Anthracycline 的藥物作用機制探討 44
九、新 Anthracycline 藥物亦能抑制其他腸病毒之 IRES 44
第四章 討論 45
第五章 圖表 48
第六章 參考文獻 57
第七章 附錄 64
附錄一、微小RNA病毒科分類(Wikipedia) 64
附錄二、腸病毒屬分類 65
附錄三、腸病毒之正股RNA基因組以及其轉譯後相對應之蛋白 65
附錄四、腸病毒之複製週期 66
附錄五、抗腸病毒71型藥物結構 67
附錄六、腸病毒71型抑制劑作用機制概要 68
附錄七、早期抗鼻病毒藥物針對病毒結構蛋白作用機轉示意圖 68
附錄八、小RNA病毒IRES分類 69
附錄九、腸病毒71型的IRES結構 69
附錄十、Anthracyclines與類其類似物之藥物結構 70
附錄十一、Idarubicin(IDR)藥物毒性的細胞毒性 71
附錄十二、Idarubicin(IDR)藥物作用機制的探討 71

圖目錄
圖 ㄧ、Idarubicin會選擇性的結合到各腸病毒的 IRES RNA 48
圖 二、Idarubicin會與 EV71 IRES RNA結合在多重位置 49
圖 三 、IDR選擇性干擾EV71 IRES RNA與hnRNPA1的結合 50
圖 四、IDR干擾各EV71 IRES RNA功能區與hnRNPA1的結合 51
圖 五、Anthracycline 類藥物對於EV71感染細胞比例的影響 52
圖 六、Alarubicin的細胞毒性 53
圖 七、New Anthracycline藥物對病毒蛋白(VP1)表現的抑制 54
圖 八、Anthracycline類藥物會選擇性抑制EV71 IRES 55
圖 九、Anthracycline類藥物對於其他腸病毒感染細胞率的影響 56



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