請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7686完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
| dc.contributor.author | Yi-Chou Huang | en |
| dc.contributor.author | 黃乙洲 | zh_TW |
| dc.date.accessioned | 2021-05-19T17:50:08Z | - |
| dc.date.available | 2022-08-25 | |
| dc.date.available | 2021-05-19T17:50:08Z | - |
| dc.date.copyright | 2017-08-25 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-16 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7686 | - |
| dc.description.abstract | 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。 | zh_TW |
| dc.description.abstract | 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. | en |
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| dc.description.tableofcontents | Table of Contents
Acknowledgement…………………………………………………………………….I Abstract in Chinese…………………………………………………………………..II Abstract in English……………………………………………………………….....III Table of Contents…………………………………………………………………….V Index of Schemes…………………………………………………………………...VII Index of Figures…………………………………………………………………...VIII Index of Tables……………………………………………………………………...XI Abbreviations……………………………………………………………………...XIII Chapter 1. Introduction……………………………………………………………...1 1.1 Influenza A virus……………………………………………………………….1 1.2 Ribonucleoprotein (RNP) and its structure………………………………….4 1.3 Virus life cycle………………………………………………………………….9 1.3.1 RNP transcription and replication…………………………………...10 1.3.2 RNP assembly………………………………………………………….14 1.3.3 Transportation of RNP into host cell…………………………………16 1.3.4 Transportation of RNP out of host cell……………………………….18 1.4 Anti-influenza drugs targeting the RNP……………………………………20 1.4.1 Interactions between RNA and RNA polymerase in RNP…………..21 1.4.2 Interactions between NP and RNA polymerase in RNP…………….22 1.4.3 Interactions between NP and viral RNA segment in RNP…………..23 1.4.4 Interactions between NP monomers in RNP…………………………24 1.5 Photoaffinity labeling………………………………………………………...27 1.6 Previous research on anti-influenza agents targeting NP trimerization….30 Chapter 2. Results and Discussion………………………………………………....34 2.1 Research motivation………………………………………………………….34 2.2 Strategy for designing effective anti-influenza drugs...................................34 2.3 Modifications at terminal amine group……………………………………..39 2.4 Synthesis of (1,1-diphenylmethyl)amino derivatives 13a and 13b………...40 2.5 Synthesis of benzylamino derivatives 22a and 22b…………………………44 2.6 Synthesis of derivatives bearing azidophenyl group for photoaffinity labeling………………………………………………………………………..45 2.7 Bioassay……………………………………………………………………….50 2.8 Conclusion…………………………………………………………………….52 2.9 Prospect……………………………………………………………………….54 Chapter 3. Experimental Section…………………………………………………..59 3.1 General part…………………………………………………………………..59 3.2 Procedure of bioassay………………………………………………………..60 3.2.1 Material and methods…………………………………………………...60 3.2.2 Determination of influenza virus TCID50………………………………60 3.2.3 Determination of EC50 of NP inhibitors………………………………..61 3.3 Synthetic procedure and characterization of compounds…………………62 References…………………………………………………………………………...95 Appendix…………………………………………………………………………...110 Index of Schemes Scheme 1. Photolysis of aryl azide…………………………………………………..29 Scheme 2. Photolysis of diazirine……………………………………………………29 Scheme 3. First synthetic strategy for (1,1-diphenylmethyl)amino derivative 13a….41 Scheme 4. Unsuccessful synthesis of compound 13a through SN2 reaction from another direction………………………………………………………….43 Scheme 5. Successful synthesis of compounds 13a (JMF4172) and 13b (JMF4195)………………………………………………………………..44 Scheme 6. Synthesis of benzylamino derivatives 22a (JMF4286) and 22b (JMF4196) ……………………………………………………………….45 Scheme 7. Synthesis of 4-azidobenzyl derivative 30 (JMF4287)……………………46 Scheme 8. Synthesis of 1-phenyl-1-(4-azidophenyl)methylamino derivative 36 (JMF4288)………………………………………………………………..47 Scheme 9. Synthesis of 1,1-bis(4-azidophenyl)methylamino derivative 42 (JMF4289)………………………………………………………………..50 Index of Figures Figure 1. Structure of influenza A virus………………………………………………2 Figure 2. Diagram of RNP structure…………………………………………………..5 Figure 3. Cryo-EM reconstruction of RNP…………………………………………...5 Figure 4. Diagram of intersubunit interactions in the RNA polymerase complex……6 Figure 5. Crystal structure of influenza A virus NP trimer…………………………...8 Figure 6. The influenza A virus life cycle…………………………………………...10 Figure 7. A model of RNP transcription and replication: (A) steps in the RNP transcription process, and (B) steps in the RNP replication process……..13 Figure 8. Directionality of NP assembly onto RNP complexes……………………..15 Figure 9. Transportation of the RNPs from virion to nucleus……………………….17 Figure 10. Transportation of the progeny RNPs out of host cell from nucleus……...19 Figure 11. Docking the atomic structure of (A) NPs and (B) RNA polymerase into the RNP model……………………………………………………………….20 Figure 12. Effect of point mutations and insertions on the RNA polymerase binding of the conserved sequences at (A) the 3’ end and (B) the 5’ end………...21 Figure 13A. The crystal structure of NP…………………………………………….22 Figure 13B. The activities of the NP mutants in the minigenome dual-luciferase assay………………………………………………………………….22 Figure 13C. The activities of the NP mutants in the vRNA template minigenome assay…………………………………………………………………...22 Figure 13D. Relative amounts of vRNA and mRNA produced by the NP mutants in the cRNA template minigenome assay………………………………..22 Figure 14. Electrostatic potential distribution of NP………………………………...23 Figure 15. Inter-subunit interactions mediated by the tail loop……………………...24 Figure 16. Viral RNA synthesis activities of NP mutants by the minigenome assay…………………………………………………………………...25 Figure 17A. Oligomerization behavior of NP tail loop mutants as shown by gel filtration chromatography……………………………………………...26 Figure 17B. Oligomerization behavior of NP D491 mutants as shown by gel filtration chromatography………………………………………………………..26 Figure 17C. RNA synthesis activities of NP mutants determined in the vRNA- and cRNA-templated minigenome assays…………………………………26 Figure 18. A cartoon representation for the process of photoaffinity labeling………28 Figure 19A. Interactions including the tail-loop (green) and its binding pocket (gold)…………………………………………………………………31 Figure 19B. Structure and inhibitory effect of compound A………………………...31 Figure 19C. The modeled structure of the NP–A complex………………………….31 Figure 20. Small molecules that inhibit viral replication via binding to NP……………………………………………………………………...32 Figure 21. NP surface map of residues affecting aryl piperazine amide efficacy……33 Figure 22. X-ray structure of C–NP complex………………………………………..33 Figure 23. The strategy for designing anti-influenza drugs based on the structure of compound A…………………………………………………………...35 Figure 24. Bioassay of compound A and its derivatives with different heterocycle core structures………………………………………………………………37 Figure 25. Bioassay of compound A analogs with various aliphatic chain lengths….38 Figure 26. Bioassay of derivatives with various terminal functional groups………...38 Figure 27. 1H NMR spectra of the presumed bromination compound (A) and crude compound 33 (B) in CDCl3 solution…………………………………...49 Figure 28. Mechanism of MTS assay and anti-influenza activity (EC50) of compounds 13a (JMF4172), 22a (JMF4286), 30 (JMF4287), 36 (JMF4288) and 42 (JMF4289)……………………………………………………………..52 Figure 29. General structural features of compound A analogs possessing anti-influenza activity……………………………………………………… 54 Figure 30. Anti-influenza activity (EC50) of compounds 43, 44, 45 and 46…………57 Figure 31. Proposed drug candidates in the future work……………………………..58 Index of Tables Table 1. Anti-influenza EC50 values (μM) of compound A analogs………………...36 Table 2. Unsuccessful SN2 reactions of compound 11………………………………42 Table 3. Attempts to prepare compound 34 by alkylation reaction of amine 24 with the presumed bromination compound…………………………………48 Table 4. Calculated partition coefficient (clogP) of the above-synthesized compound A analogs with various R1 and R2 substituents on terminal amine group…………………………………………………………………...56 | |
| dc.language.iso | en | |
| dc.title | 以抑制核蛋白三聚體之生成設計及合成抗流感藥物 | zh_TW |
| dc.title | Design and Synthesis of Anti-influenza Drugs by Inhibiting the Formation of Nucleoprotein Trimer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 羅禮強(Lee-Chiang Lo),王宗興(Tsung-Shing Wang),鄭婷仁(Ting-Jen Cheng) | |
| dc.subject.keyword | 抗流感藥物,核蛋白, | zh_TW |
| dc.subject.keyword | Anti-influenza Drugs,Nucleoprotein, | en |
| dc.relation.page | 145 | |
| dc.identifier.doi | 10.6342/NTU201702777 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2017-08-17 | |
| 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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