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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 方俊民 | |
dc.contributor.author | Peng-Cheng Wang | en |
dc.contributor.author | 王鵬程 | zh_TW |
dc.date.accessioned | 2021-07-11T14:40:13Z | - |
dc.date.available | 2022-02-21 | |
dc.date.copyright | 2017-02-21 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2017-01-16 | |
dc.identifier.citation | 第五章:參考文獻
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78033 | - |
dc.description.abstract | 流行性感冒是由流感病毒所引起的急性呼吸道疾病,長期以來不斷危害全球人類的健康,由於流感病毒不斷突變,且隨時有造成大流行的可能性,因此,開發嶄新的流感藥物變得相當重要。目前抗流感藥物主要分為離子通道蛋白抑制劑與神經胺酸酶(NA)抑制劑,由於流感病毒NA subtypes的作用位置相當守恆,很多藥物開發者根據此NA保守作用區來開發流感藥物。美國食品暨藥物管理局目前已通過的流感藥物包含zanamivir (ZA), oseltamivir (OS)與peramivir (PE)。
本實驗過去分別開發出tamiphosphor (TP, 20)與zanaphosphor (ZP, 27),這兩個化合物主要是運用生物等配體的概念將oseltamivir carboxylate (OC, 14)與ZA (3)的羧酸官能基以磷酸取代,利用磷酸上有較多的氫氧基與NA中S1區域的Arg118, Arg292與Arg371產生更多的靜電吸引力,藉此提升其抑制NA的能力與保護細胞免於受到病毒感染的能力。 有鑑於克流感的抗藥性問題已發生多年,因此,開發可對抗突變株病毒的流感藥物變得相當急迫。本研究的第一部分是合成peramivir之生物等配物,期望研發出抗突變株病毒的流感藥物。不如我們預期的,磷酸生物等配物peraphosphor (28)抑制NA的效果比peramivir差,但此化合物對於H3N2、H5N1與H7N9的病毒仍保有很強的NA抑制能力。另外,磷酸脫水化合物46對於H1N1與H5N1病毒的NA抑制能力最好,其活性與GS4071相當。除此之外,單磷酯化合物保護細胞免於受到病毒感染的能力較其相對應的磷酸化合物好。 感染H5N1的流感病患之死亡率相當高,主要原因是病毒感染宿主細胞後會引發cytokine storm,迅速的發炎反應導致宿主細胞的防禦能力降低,因此,如何同時抑制流感病毒與過多的發炎反應變得相當重要。以往本實驗室開發的雙標靶抗流感藥物,在瑞樂沙的C7位置以酯鍵連接咖啡酸的共軛化合物72除了保留NA的抑制效果並且能夠抑制發反應,具有良好的抗流感與抗發炎效果。 本論文之第二部分主要是根據此研究成果,設計與合成peramivir與咖啡酸的共軛化合物,期望開發出同時具有抗流感與抗發炎的口服流感藥物。實驗結果顯示這些共軛化合物的抗發炎能力相當弱,但在NA抑制與抗流感病毒的活性測試都展現相當優異的效果,其中以醯胺共軛化合物87的NA抑制能力、抗流感病毒能力與保護小鼠免於受到病毒感染的效果最好,預期此化合物有機會以口服餵藥成為嶄新的抗突變株H275Y流感藥物。 | zh_TW |
dc.description.abstract | Influenza is an acute respiratory diseases caused by influenza virus. Influenza has affected human health worldwide for a long time. The development of novel anti-influenza agents is important because influenza virus frequently mutate and may result in pandemic infection. There are two classes of anti-influenza drugs by targeting the M2 ion channel or neuraminidase (NA) of influenza viruses. Because the structures of NA active sites are rather conserved, many drug companies develop anti-influenza drugs based on this conserved active sites. Three NA inhibitors zanamivir (ZA), oseltamivir (OS) and peramivir (PE) have been approved by FDA for use as anti-influenza drugs.
Our lab have previously developed tamiphosphor (TP, 20) and zanaphosphor (ZP, 27) as the phosphonate congeners of ZA and oseltamivir carboxylate (OC). By replacing the carboxylate group in ZA and OC with a phosphonate group, TP and ZP show more potent NA inhibition and better protection of host cells from influenza viral infection since phosphonate ion in ZP and TP exhibits more extensive electrostatic interactions with the three arginine residues (R118, R292 and R371) in the active site of NA. Since oseltamivir-resistant viruses have occurred over the years, it is urgent to develop new anti-influenza drugs that can inhibit oseltamivir-resistant strains. We have synthesized a series of PE bioisosteres aiming to combat oseltamivir-resistant viruses. Peraphosphor (PP, 28) unexpectedly has inferior NA inhibitory activity to PE. However, this compound is a potent NA inhibitor against H3N2, H5N1 and H7N9 viruses. The NA inhibitory activity of PP dehydration compound (46) is comparable to that of OC for H1N1 and H5N1 viruses. All the phosphonate monoalkyl esters exhibit superior anti-influenza activities to their parent phosphonic acids. The high mortality of human infected by H5N1 virus has been attributed to the excessive induction of a severe cytokine storm which reduced the defense ability of host cell. It is important to develop anti-influenza agents for simultaneous inhibition of influenza virus NA and suppression of pro-inflammatory cytokines. Our lab Kung-Cheng Liu has explored the novel dual-targeted bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. In particular, the caffeic acid bearing ZA conjugates by ester linkage (72) showed simultaneous inhibition of influenza virus neuraminidase and suppression of pro-inflammatory cytokines. Based on these results, we designed and synthesized a series of caffeic acid bearing PE conjugates aiming to develop oral anti-influenza drugs with anti-inflammatory activity. The cytokines suppression experiments showed that the inhibitory activities of cytokines of these PE conjugates are poor. However, the NA inhibition and anti-influenza activities of these PE conjugates are excellent, especially for amide conjugates (87). This compound provided remarkable protection of mice against influenza infections. It has potential to become a novel oral anti-influenza drug for treatment of H275Y resistant strain virus. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T14:40:13Z (GMT). No. of bitstreams: 1 ntu-105-F99223110-1.pdf: 19717920 bytes, checksum: d2ec41ffd2af884b79b6e1b8ef8f3e6b (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 目錄
摘要 I Abstract III 目錄 VI 圖目錄 X 表目錄 XIII 流程目錄 XV 簡稱用語對照表 XVII 第一章:緒論 1 1-1. 流感 1 1-1-1. 流感症狀 1 1-1-2. 流感的歷史背景 1 1-1-3. 流感病毒的結構 2 1-1-4. 流感病毒感染宿主細胞的生命週期(life cycle) 3 1-2. 流感病毒表面的重要蛋白 5 1-2-1. 血液凝集素(Haemagglutinin,HA) 5 1-2-2. 神經胺酸酶(Neuraminidase, NA) 6 1-2-3. M2 離子通道(ion channel) 7 1-3. 流感藥物的開發 9 1-3-1. 血液凝集素(HA)抑制劑 10 1-3-2. M2 離子通道(ion channel)抑制劑 10 1-3-3. 神經胺酸酶(Neuraminidase, NA)抑制劑 11 1-3-3-1. Zanamivir與Laninamivir的開發 12 1-3-3-2. Oseltamivir的開發 15 1-3-3-3. Peramivir的開發 17 1-4. 新型流感抑制劑的開發 19 1-4-1. 病毒的突變 19 1-4-2. 流感病毒的抗藥性 20 1-4-2-1. H274Y突變 21 1-4-2-2. R292K突變 22 1-4-2-3. E119G突變 24 1-4-3. Tamiphosphor的開發 25 1-5. 新型抗流感藥物的開發 28 1-5-1. 生物等配物(bioisostere) 29 1-5-2. 羧酸的非典型生物等配物 29 1-5-2-1. 有機磷酸(phosphonic acid)與次磷酸(phosphinic acid) 30 1-5-2-2. 磺酸(sulfonic acid)與亞磺酸(sulfinic acid) 30 1-5-2-3. 磺胺(sulfonamide)與磺醯亞胺(sulfonimide, acyl sulfonamide) 30 1-5-3. 新型抗流感藥物的開發策略 31 1-6. 抗流感活性測試方法 32 第二章:設計與合成嶄新帕拉米弗生物等配體以抑制流感神經胺酸酶 35 2-1. 設計概念 35 2-2. Peramivir的合成 35 2-3. Peraphosphor的逆合成分析 36 2-4. 生物等配物有機磷酸與單乙基磷酯化合物的合成 37 2-5. 生物等配物磺酸與磺胺化合物的合成 50 2-6. 抗流感活性的測試 54 2-7. Peraphosphor 28的構型探討 57 2-8. 分子模擬(Molecular modeling) 59 2-9. 單己基磷酯化合物的合成 61 2-10. 抗流感活性的測試與脂溶性討論 63 2-11. 測試單乙基磷酯化合物47的水解 69 2-12. 結論 70 第三章:合成帕拉米弗共軛衍生物作為有效的口服抗流感試劑 73 3-1. 緒論 73 3-1-1. 抗流感與抗發炎的合併治療 73 3-1-2. 發炎反應 73 3-1-3. 抗發炎藥物 74 3-1-4. 咖啡酸衍生物與抗發炎 75 3-1-5. 瑞樂沙共軛衍生物對流感病毒的雙標靶治療 76 3-2. 結果與討論 77 3-2-1. 設計概念 77 3-2-2. 酯鍵共軛化合物82與醯胺鍵共軛化合物87的合成 78 3-2-3. 醚鍵共軛化合物98的合成 80 3-3. 抗流感活性的測試與脂溶性討論 85 3-4. 抗發炎化合物的合成 90 3-5. 抗發炎活性 91 3-5-1. 抗發炎活性測試方法 91 3-5-2. 抗發炎活性測試結果與討論 92 3-6. 老鼠存活率實驗 94 3-6-1. 老鼠存活率實驗方法 94 3-6-2. 化合物對老鼠的保護效果比較 95 3-7. 結論 100 第四章:實驗部分 102 4-1. General part 102 4-2. Procedure of bioassay 103 4-2-1. Material and methods 103 4-2-2. Determination of influenza virus TCID50 104 4-2-3. Cloning, Expression, and Purification of Influenza neuraminidases (NAs) 105 4-2-4. Determination of neuramindase activity by a fluorescent assay 105 4-2-5. Determination of IC50 of NA inhibitor 106 4-2-6. Determination of EC50 and CC50 of NA inhibitor 106 4-2-7. Cytokine determination by ELISA 107 4-2-8. In Vivo assay 107 4-3. Computer modeling 108 4-4. Procedure of stability studies 109 4-4.1. Chemical stability studies 109 4-4.2. Stability test in rabbit serum 109 4-5. Synthetic procedures and characterization of compounds 110 第五章:參考文獻 194 附錄 213 圖目錄 圖一、A型流感病毒基本結構 3 圖二、流感病毒複製過程及相對應的抑制劑 4 圖三、禽流感與人流感病毒血液凝集素的受體末端結構 6 圖四、神經胺酸酶水解宿主表面唾液酸的示意圖 6 圖五、神經胺酸酶水解唾液酸受體的機制 7 圖六、M2離子通道蛋白的結構 8 圖七、M2離子通道蛋白的作用機制 9 圖八、TBHQ與HA的結合位置 10 圖九、M2離子通道蛋白與抑制劑可能的結合位置 11 圖十、神經胺酸酶與DANA的共結晶示意圖 13 圖十一、神經胺酸酶與GS4071 (14)的共結晶示意圖 16 圖十二、DANA與化合物17在N9神經胺酸酶活性中心的疊合圖 18 圖十三、神經胺酸酶與peramivir (6)的共結晶示意圖 19 圖十四、流感病毒的基因重組 20 圖十五、(a) GS4071 (14)在H274Y神經胺酸酶的空間結構圖; (b) zanamivir (3)在H274Y神經胺酸酶的空間結構圖; (c) peramivir (6)在H274Y神經胺酸酶的空間結構圖 22 圖十六、(a) GS4071 (14)在野生型H11N9神經胺酸酶的空間結構圖; (b) GS4071 (14)在突變株H11N9-R292K神經胺酸酶的空間結構圖,青色:X-ray實驗的結構圖,白色:電腦模擬的快照圖(snapshots) 23 圖十七、Peramivir (6)在H7N9突變株R292K神經胺酸酶的快照圖(snapshots),(a) 時間:20-40 ns,(b) 時間:40-70 ns,青色:X-ray實驗的結構圖,白色:電腦模擬的快照圖(snapshots) 23 圖十八、Zanamivir (3)在(a) H11N9,(b) H7N9,(c) H7N9-R292K突變株的電腦模擬結構 24 圖十九、(a) 野生型NA–zanamivir複合體(黃色)與E119G NA–zanamivir複合體 (青色)的疊合圖;(b) 野生型NA–peramivir複合體 (黃色)與E119G NA–peramivir複合體 (青色)的疊合圖;(c) 野生型NA–GS4071複合體 (黃色)與E119G NA–GS4071複合體 (青色)的疊合圖,野生型NA是指H1N1病毒 25 圖二十、(a) GS4071(14)位於神經胺酸酶活性中心的電腦分子模擬示意圖; (b) Tamiphosphor (20)位於神經胺酸酶活性中心的電腦分子模擬示意圖(N1 subtype, PDB code: 2HU4) 26 圖二十一、MUNANA在NA活性測試中釋放螢光訊號的機制 33 圖二十二、CellTilter 96 aqueous non-radioactive cell proliferation assay 34 圖二十三、碘化合物34的X-ray繞射圖 40 圖二十四、環氧丙烷化合物35的X-ray繞射圖 41 圖二十五、利用COSY與NOESY NMR判斷異構物36a與36b之結構:(A) COSY of 36a; (B) NOESY of 36a; (C) COSY of 36b; (D) NOESY of 36b 44 圖二十六、磷酸化合物28的X-ray繞射圖 46 圖二十七、利用COSY與NOESY NMR判斷異構物53a與53b之結構:(A) COSY of 53a; (B) NOESY of 53a; (C) COSY of 53b; (D) NOESY of 53b 52 圖二十八、磺酸化合物55的X-ray繞射圖 53 圖二十九、Peramivir 6 (A)、peraphosphor 28 (B)、脫水的磷酸化合物46 (C)與單乙基磷酯化合物38 (D)在NA活性中心之分子模擬計算,綠色虛線為氫鍵作用力(N1 subtype, PDB code:2HU4) 60 圖三十、Peramivir 6 (粉紅色)、peraphosphor 28 (淡藍色)、脫水的磷酸化合物46 (黃色)在NA活性中心 (N1 subtype, PDB code:2HU4)之分子模擬疊合圖,與peramivir–NA complex (紫色)的構型比較 (PDB code:1L7F) 60 圖三十一、共軛化合物82、87與oseltamivir (16)治療小鼠感染H1N1病毒(A/WSN/1933/H1N1)之存活率 96 圖三十二、共軛化合物82、87與oseltamivir (16)治療小鼠感染H1N1病毒(A/WSN/1933/H1N1)之體重變化 97 圖三十三、共軛化合物82、87與oseltamivir (16)治療小鼠感染H1N1變異株(A/WSN/1933/H275Y/H1N1)之存活率 99 圖三十四、共軛化合物82、87與oseltamivir (16)治療小鼠感染H1N1變異株(A/WSN/1933/H275Y/H1N1)之體重變化 100 表目錄 表一、近百年來的流感大流行 2 表二、Zanamivir (3)、peramivir (6)與GS4071 (14)對野生型(A/WSN/33)、突變株(A/WSN/33/H274Y)神經胺酸酶病毒株的抑制能力 21 表三、GS4071 (14)、化合物20與21針對神經胺酸酶的抑制活性、抗流感病毒活性與細胞毒性 26 表四、Tamiphosphor (20)及衍生物21-23針對數種流感病毒的NA抑制活性測試IC50 (nM) 27 表五、Tamiphosphor (20)及衍生物21-23的抗流感病毒活性測試EC50 (μM) 28 表六、在不同條件下,將環氧丙烷35開環得到磷酯36a 41 表七、化合物28、38、42、46、47、51、52、55與58針對NA的抑制活性和抗流感病毒之活性 55 表八、化合物28、38、42、46、47、51、52、55與58針對H275Y突變株NA的抑制活性和抗流感病毒之活性 56 表九、Peraphosphor (28)的1H NMR光譜assignment 57 表十、比較NMR、X-ray與分子模擬所得到peraphosphor (28)的torsional angles 58 表十一、化合物61、65、69與peraphosphor衍生物針對NA的抑制活性、抗流感病毒之活性、clog P及clog D 65 表十二、化合物61、65、69與peraphosphor衍生物針對H275Y突變株NA的抑制活性和抗流感病毒之活性 67 表十三、化合物28、46與47針對更多病毒之NA抑制能力(IC50, nM) 68 表十四、嘗試合成胺類化合物91 82 表十五、嘗試合成醚鍵共軛化合物98的不同反應條件 84 表十六、化合物82、87、98與99針對NA的抑制活性、抗流感病毒之活性、clog P及clog D 86 表十七、化合物82、87、98與99針對H275Y突變株NA的抑制活性和抗流感病毒之活性 88 表十八、共軛化合物87與99針對更多病毒之NA抑制能力(IC50, nM) 89 表十九、化合物抑制細胞激素IL-6、TNF-α與IFN-γ之活性 93 表二十、共軛化合物82、87與oseltamivir (16)治療小鼠感染H1N1病毒之存活率 95 表二十一、共軛化合物82、87與oseltamivir (16)治療小鼠感染H1N1變異株之存活率 98 流程目錄 流程一、Chand團隊報導peramivir (6) 的合成方法…………………….………..35 流程二、Peraphosphor (28)的逆合成分析………………………………………… 36 流程三、烯類化合物29與nitrile oxide的(3+2)環化反應:(A)參考Chand報導的方法; (B)參考Miller報導的方法; (C)縮短反應時間的方法… ……………………………………………………………………….37 流程四、Vince lactam與nitrile oxide的(3+2)環化反應………………………….. 37 流程五、最佳化乙醯胺31的合成途徑…………………………………………… 38 流程六、環氧丙烷化合物35的合成途徑…………………………………………. 39 流程七、Peraphosphor (28)與單乙基磷酯 (38)的合成途徑………………………. 44 流程八、化合物42的合成途徑……………………………………………………. 46 流程九、Peraphosphor的脫水化合物46與其單乙基酯47的合成途徑………… 47 流程十、Deoxy-peraphosphor 51與其單乙基酯52的合成途徑…………………. 48 流程十一、嘗試利用碘化鋰水解去保護後的磷酯化合物……………………….. 48 流程十二、Peramivir磺酸化合物55的合成途徑…………………………………. 52 流程十三、Peramivir磺胺化合物58的合成途徑…………………………………. 53 流程十四、Peraphosphor單己基磷酯61的合成途徑…………………………….. 61 流程十五、Dehydrated peraphosphor單己基酯65的合成途徑…………………..61 流程十六、Deoxy-peraphosphor單己基酯69的合成途徑……………………….. 62 流程十七、三氟醋酸胺鹽化合物79的合成途徑…………………………………. 77 流程十八、酯鍵共軛化合物82的合成途徑………………………………………. 78 流程十九、三氟醋酸胺鹽化合物85的合成途徑…………………………………. 79 流程二十、醯胺鍵共軛化合物87的合成途徑…………………………………….. 79 流程二十一、醚類化合物90的合成途徑………………………………………….. 80 流程二十二、胺類化合物91的合成途徑………………………………………… 82 流程二十三、化合物97的合成途徑………………………………………………. 82 流程二十四、共軛化合物99的合成途徑………………………………………….. 84 流程二十五、化合物102與103的合成途徑…………………………………….. 90 流程二十六、化合物70與104的合成途徑………………………………………. 90 | |
dc.language.iso | zh-TW | |
dc.title | 設計與合成帕拉米弗衍生物作為有效抗流感試劑 | zh_TW |
dc.title | Design and Synthesis of Peramivir Derivatives as Effective Anti-influenza Agents | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 楊圖信,吳宗益,羅禮強,林俊宏,謝俊結 | |
dc.subject.keyword | 流感藥物,生物等配物, | zh_TW |
dc.subject.keyword | anti-influenza drugs,bioisosteres, | en |
dc.relation.page | 348 | |
dc.identifier.doi | 10.6342/NTU201601344 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-01-17 | |
dc.contributor.author-college | 理學院 | zh_TW |
dc.contributor.author-dept | 化學研究所 | zh_TW |
顯示於系所單位: | 化學系 |
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