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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張淑媛(Sui-Yuan Chang) | |
dc.contributor.author | Yi-Feng Chang | en |
dc.contributor.author | 張譯丰 | zh_TW |
dc.date.accessioned | 2021-06-15T16:11:27Z | - |
dc.date.available | 2020-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52304 | - |
dc.description.abstract | 目前治療流感病毒的第一線藥物以neuraminidase inhibitor(NAI)為主,包括oseltamivir(俗稱克流感)、zanamivir、及peramivir 等。NAI是唾液酸(sialic acid)的類似物,會與sialic acid競爭NA酵素活性位,進而阻止病毒顆粒的釋出。但隨著藥物使用的頻繁, 流感病毒的NA也會產生位點突變而具有抗藥性,如2008年流行的H1N1克流感抗藥性病毒株。2013年3月在中國所爆發的H7N9疫情,在臨床上也觀察到抗藥性H7N9,抗藥性位點主要源自於NA 產生E115V或 R289K等突變,進而增加治療的困難,所以發展出比現行藥物更具效力的合成物是相當重要的。本實驗主要目的在於篩選出對於具抗藥性之流感病毒有較佳抑制效果的合成物。首先利用自病人體內所分離出的流感病毒株(為mix population)以plaque reduction assay先將來自中研院的177個合成物進行初步篩選,並選擇有明顯抑制效果以及能使plaque面積縮小的合成物做進一步測試。同時將溶斑純化(plaque purify)所得的病毒株送定序確認NA序列,分別純化出NA帶有E115V或R289K抗藥性位點以及沒有任何位點改變(WT)的流感病毒株。以純化所得的三株流感病毒株篩選第一階段所選擇的合成物,同時與現行藥物之抑制效果做比較,觀察到部分測試的合成物確實具有較好的抑制效果。而接著決定對於三株病毒株皆有良好抑制效果的合成物之EC50與IC50,並將兩者的結果相互比較。同時也以合成物測試對於具克流感抗藥性之H1N1病毒株(6706 ,具H275Y抗藥性位點),並觀察到有六個藥物具有較佳的抑制能力。目前已篩選出16個合成物能有效抑制抗藥性流感病毒株, 其EC50及IC50與現行藥物相比較也有大幅的差異。 | zh_TW |
dc.description.abstract | Neuraminidase inhibitors (NAIs) are the first line antiviral agent in treating influenza virus infection which including oseltamivir (Tamiflu)、zanamivir (Relenza) and peramivir (Rapivab). NAI is a structure analogue of sialic acid, the receptor for influenza virus infection. NAIs can inhibit virus replication by competing with sialic acid. Although major mutations contributing to oseltamivir resistance have been shown to attenuate viral replication capability, the appearance of some compensatory mutations can alleviate the influences of major mutations. The most famous example is the oseltamivir-resistant H1N1 spread in 2008.The arising of a novel H7N9 avian influenza virus was noted in eastern China in 2013 and has caused large number of death. During the outbreak, some drug resistant H7N9 virus strains were identified, such as E115V or R289K mutations in the neuraminidases enzyme active sites. The presence of oseltamivir resistant viruses has posted great challenges in clinical management, which makes it important to develop new drugs. In this study, we used plaque reduction assay to screen anti-viral activity of the 177 compounds from Dr. Cheng of Genomics Research Center. The compounds which can reduce the plaque size and/or have obvious inhibitory effects on viral plaque formation were selected for further confirmation. At the same time, the oseltamivir-resistant virus strains with the E115V or R289K mutation on the NA sequence were isolated by plaque purification, and were used to confirm the antiviral effect of the compounds selected in the first stage. Comparing with the results between the compounds and clinical drugs, some of the compounds have better inhibitary effects. The EC50 and IC50 、EC90 and IC90 of the selected compounds which showed efficient inhibition of all three viruses were determined. These compounds also have inhibitary effects to oseltamivir-resistant H1N1. In summary, we found that 16 compounds had better inhibitory effect to drug-resistant influenza viruses than clinical drugs. The EC50 and IC50 of these compounds are lower than that of oseltamivir. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T16:11:27Z (GMT). No. of bitstreams: 1 ntu-104-R02424022-1.pdf: 1843098 bytes, checksum: 9712e45e0f688ece60c872ad1550a165 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 致謝 I 中文摘要 II 英文摘要 III 表目錄 VII 圖目錄 VIII 第一章 序論 1 1.1 流感病毒介紹 1 1.1-1. 流感病毒之重要大流行 1 1.1-2. 流感病毒之構造簡介 2 1.1-3. 流感病毒之感染模式 2 1.2 抗流感病毒用藥之發展 5 1.2-1 M2通道蛋白合成物 (M2 ion-channel inhibitor) 5 1.2-2 神經胺酸酶合成物(Neuraminidase inhibitor‚NAI) 6 1.3抗藥性流感病毒之出現 7 1.3-1. M2合成物之抗藥性病毒株 7 1.3-2. 神經胺酸脢合成物之抗藥性病毒株 8 1.4 新型H7N9禽流感病毒 9 1.4-1. 疫情簡介 9 1.4-2. 病毒基因重組來源 10 1.4-3. 台灣境外移入病毒株 11 第二章 實驗方法 12 2.1實驗方法 12 2.1-1. MDCK細胞株培養 12 2.1-2 流感病毒培養 12 2.1-3 溶斑試驗(Plaque assay) 12 2.1-4 溶斑減少中和試驗(Plaque reduction assay) 13 2.1-5 懸浮病毒液中的病毒RNA萃取 13 2.1-6 病毒RNA反轉錄反應(Reverse transcription reaction) 14 2.1-7 NA序列之聚合酶鏈鎖反應(Polymerase chain reaction) 14 2.1-8 NA序列分析 15 2.1-9 神經胺酸脢合成物敏感度試驗(Neuraminidase inhibitor susceptibility test NAI assay) 15 2.1-10溶斑純化(plaque purification) 16 2.1-11 蔗糖梯度離心濃縮病毒顆粒(Sucrose gradient centrifugation) 16 第三章 實驗結果 17 3.1 新合成之合成物對混合株(mix population)H7N9抑制效果 17 3.2 純化NA序列具有E115V或R289K點突變H7N9病毒株 17 3.3 新合成合成物對具NAI抗藥性H7N9病毒株之抑制效果 18 3.4 新合成合成物之EC50及IC50 / EC90及IC90 18 3.5 新合成合成物對抗藥性H1N1之抑制效果 19 第四章 討論 21 第五章 參考文獻 26 | |
dc.language.iso | zh-TW | |
dc.title | 克流感抗藥性病毒株神經胺酸脢合成物類似物之篩選與鑑定 | zh_TW |
dc.title | Screening and identification of neuraminidase inhibitor analogues against oseltamivir-resistant influenza virus | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 高全良(Chuan-Liang Kao),李君男(Chun-Nan Lee),劉旻禕,施信如 | |
dc.subject.keyword | 克流感抗藥性病毒株,神經胺酸脢抑制物, | zh_TW |
dc.subject.keyword | Resistant-influenza virus,NAI, | en |
dc.relation.page | 61 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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