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研究生:林俊光
研究生(外文):Chun-kuang Lin
論文名稱:海洋天然物之抗病毒藥物開發與藥物標靶之探討
論文名稱(外文):Development of antiviral drugs from marine natural products and investigation of drug target against virus
指導教授:廖志中廖志中引用關係
指導教授(外文):Chih-Chuang Liaw
學位類別:博士
校院名稱:國立中山大學
系所名稱:海洋生物科技博士學位學程
學門:自然科學學門
學類:海洋科學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:187
中文關鍵詞:絲氨酸蛋白水解酶表皮生長因子受體第二型環氧合酶海洋天然物C型肝炎病毒登革病毒
外文關鍵詞:DENVCOX-2marine natural productEGFRprostasinHCV
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C型肝炎病毒(Hepatitis C Virus; HCV)感染會造成慢性肝發炎,進而造成肝硬化及肝癌。登革熱病毒(dengue virus; DENV)感染導致急性自身的登革熱甚至造成威脅生命的出血性登革熱及登革休克症候群。本論文的目的是從海洋天然物中找尋抗病毒藥物,並且探討細胞內因子對於登革病毒複製之影響。為了找到具有潛力的抗病毒藥物,我們發現從海茄冬萃取出的betulinic acid (BA)及acteoside (AM-4)能夠抑制HCV複製,BA抑制HCV病毒複製的機轉是透過降低NF-κB及MAPK-ERK1/2所調控的第二型環氧合酶(cyclooxygenase-2, COX-2);AM-4抑制HCV病毒感染是透過阻擋病毒進入細胞及病毒透過細胞與細胞之間的感染。更進一步,我們發現從軟珊瑚萃取出的lobohedleolide能夠透過降低HCV誘導的COX-2表現而抑制病毒複製,藉由數個刪除COX-2啟動子的luciferase冷光報導載體,我們首先發現CCAAT/enhancer-binding protein (C/EBP)對lobohedleolide降低COX-2表現是一個重要的轉錄因子,而lobohedleolide抑制HCV誘導的C/EBP表現是透過降低JNK及c-Jun磷酸化所造成的。值得注意的是,我們發現BA、AM-4及lobohedleolide在與臨床治療HCV的藥物進行合併治療能夠以加成反應方式抑制HCV複製,這結果指出這三個天然物具有高的生物醫學潛力成為控制HCV的輔助藥物。此外,我們發現BA及lobohedleolide亦具有抑制登革病毒複製的活性。為了從細胞基因中尋找抗DENV的治療標靶,我們從臨床登革病人檢體中我們發現COX-2表現量較健康者高,接著在DENV感染的ICR乳鼠中觀察到COX-2表現量提升,而當COX-2基因靜默或活性受到抑制時DENV複製就受到抑制,在ICR乳鼠模式中,我們發現COX-2抑制劑NS398能夠保護乳鼠免於危及生命的DENV感染,這些結果顯示針對COX-2是一個很好的方式去控制DENV感染。更進一步,我們從臨床登革病人檢體中發現絲氨酸蛋白水解酶prostasin表現量較健康者低,而當我們大量表現prostasin基因時能夠降低ICR乳鼠受到DENV感染造成的生存率下降並且能夠抑制DENV複製,我們更進一步發現prostasin抑制DENV複製是透過蛋白質水解切割表皮生長因子受體(epithelial growth factor receptor, EGFR),而prostasin水解切割活性是依賴著matriptase及hepatocyte growth factor activator inhibitor type 2 (HAI-2)表現量。這些結果指出COX-2及prostasin有高度成為抗登革病毒的標靶基因的潛力。
Hepatitis C virus (HCV) infection causes chronic inflammation of liver, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Infection of dengue virus (DENV) caused diseases ranging from acute self-limiting febrile illness to life-threatening dengue hemorrhagic fever and dengue shock syndrome. The purposes of present dissertation are to discover the anti-viral agents from marine natural products and to investigate the impact of cellular factors on DENV replication. For finding the potential antivirals, we found that betulinic acid (BA) and acteoside (AM-4) extracted from Avicennia marina could reduce HCV replication. The mechanism study demonstrated that BA reduced HCV replication through decreasing the NF-κB- and ERK1/2-mediated cyclooxygenase-2 (COX-2) expression. The AM-4 suppressed HCV infection by blocking viral entry into cells and cell-to-cell spread of HCV. In addition, we identified that lobohedleolide extracted from soft coral exhibited anti-HCV activity by suppression of HCV-induced COX-2 expression. Using various COX-2 promoter deletion constructs linked to luciferase reporter gene, we first identified CCAAT/enhancer-binding protein (C/EBP) as a key transcription factor for the down-regulation of COX-2 by lobohedleolide, and then demonstrated that the HCV-induced C/EBP expression could be suppressed by lobohedleolide through inhibiting the phosphorylation of JNK and c-Jun. Notably, combination treatment of BA, AM-4 and lobohedleolide with several clinically used HCV drugs synergistically inhibited HCV RNA replication, indicating that these three natural products exhibited a high biomedical potential to be used as a supplementary agent for control of HCV infection. Besides, BA and lobohedleolide also exhibited anti-DENV activity. For finding the therapeutic targets from cellular gene against DENV, we observed an increased level of COX-2 in patients with dengue fever compared with healthy individuals. Then, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. Using ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection, revealing targeting COX-2 is a promising strategy to control DENV infection. In addition, we found that the expression of prostasin, a serine protease, is lower in patients with dengue fever than in healthy individuals. Exogenous expression of prostasin could protect ICR suckling mice from life-threatening DENV-2 infection and reduce DENV-2 propagation in Huh-7 cells. We further revealed that prostasin reduced DENV replication through proteolytic cleavage of epithelial growth factor receptor (EGFR). The activity of proteolytic cleavage of prostasin is dependent on the expression of matriptase and hepatocyte growth factor activator inhibitor type 2 (HAI-2). Collectively, COX-2 and prostasin exhibited highly potential to serve as therapeutic targets against DENV replication.
論文審定書 i
論文公開授權書 ii
致謝 iii
中文摘要 iv
Abstract vi
Catalogue viii
Objective 1
Chapter 1. Background 2
1-1. The virology of hepatitis C virus 2
1-2. Process of HCV entry 2
1-3. Current therapy of HCV 3
1-4. The virology of dengue virus (DENV) 4
1-5. The epidemiology of DENV 4
1-6. Pathogenesis and current therapy of DENV 5
1-7. The introduction of cyclooxygenase-2 (COX-2) and the relationship between HCV and COX-2 5
1-8. The relationship between DENV and COX-2 6
1-9. The introduction of Prostasin 6
1-10. The role of EGFR signaling on viral infection 7
1-11. The introduction of betulinic acid (BA) extracted from Avicennia marina (Fork) Vierh. 8
1-12. The introduction of three phenylethanoid glycosides extracted from Avicennia marina (Fork) Vierh. 9
1-13. The introduction of Lobohedleolide extracted from soft coral Lobophytum crassum. 9
Chapter 2. Material and Method 11
2-1. Ethics statement 11
2-2. COX-2, PEG2, and prostasin level in healthy donors and DENV patients 11
2-3. Cell Culture 12
2-4. Reagents 12
2-5. Preparation of BA 13
2-6. Preparation of lobohedleolide. 14
2-7. HCV particle preparation and infection assay. 14
2-8. DENV preparation and infection assay 14
2-9. Western blotting. 15
2-10. Real-time quantitative PCR (RT-qPCR) assay. 16
2-11. Cytotoxicity assay. 16
2-12. Transfection and luciferase activity assay. 16
2-13. PGE2 assay 17
2-14. Preparation of cytoplasmic and nuclear fractions 17
2-15. Analysis of the drug synergism. 18
2-16. Plaque assay 19
2-17. Anti-DENV-2-induced lethality of NS398 in an ICR suckling mouse model 19
2-18. Anti-DENV-2-induced lethality of prostasin in an ICR suckling mouse model 20
2-19. DENV-infection in AG129 mice 20
2-20. Statistical analysis 21
Chapter 3. Results 22
Development of antiviral drug from marine natural products 22
3-1. Betulinic acid (BA) bioactivity on HCV replication 22
3-1-1. BA inhibits HCV replication in the HCV replicon, HCV JFH-1-infected Huh7.5 cells and primary human hepatocytes 22
3-1-2. BA down-regulates COX-2 expression in HCV replicon, HCV JFH-1-infected Huh7.5 cells and primary human hepatocytes 23
3-1-3. BA inhibits HCV replication by suppressing COX-2 expression 24
3-1-4. BA-induced down-regulation of COX-2 expression correlates with blocking NF-κB signaling and the activation of MAPK-ERK1/2 25
3-1-5. BA synergistically inhibits HCV replication in combination treatment with various HCV inhibitors 26
3-2. Bioactivity of similar structure compounds of BA on DENV replication 27
3-3. Lobohedleolide bioactivity on HCV replication 27
3-3-1. Lobohedleolide reduces HCV replication in both HCV replicon and infectious system 27
3-3-2. Lobohedleolide suppresses HCV replication through inhibiting HCV-induced COX-2 expression and its activity 28
3-3-3. Lobohedleolide inhibits C/EBP transcription factor activity 30
3-3-4. Lobohedleolide reduces HCV-induced C/EBP expression, c-Jun phosphorylation, and the activation of JNK 31
3-3-5. Combination treatment of Lobohedleolide with various HCV inhibitors synergistically reduces HCV replication 32
3-4. Lobohedleolide bioactivity on DENV replication 33
3-4-1. Lobohedleolide reduced DENV protein expression and RNA replication. 33
3-4-2. Lobohedleolide delayed lethality from life-threatening DENV-2 infection in ICR suckling mice 33
3-5. Acteoside (AM-4) bioactivity on HCV entry 34
3-5-1. AM-4 reduced HCV infection through blocking virus entry but not replication 34
3-5-2. AM-4 blocked HCV entry but not RNA replication and viral assembly 34
3-5-3. AM-4 inhibited the early attachment step of HCV entry 35
3-5-4. AM-4 blocked cell-to-cell spread of HCV 36
3-5-5. AM-4 did not downregulate HCV binding receptors 37
3-5-6. Combination treatment of AM-4 with other antiviral agents promoted better viral clearance 37
Investigation of drug targeting genes against virus 38
3-6. Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents 38
3-6-1. COX-2 levels are elevated in patients with DF 38
3-6-2. DENV infection induces COX-2 expression in ICR suckling mice 38
3-6-3. DENV infection induces COX-2 expression and PGE2 production in hepatoma cells 39
3-6-4. COX-2 overexpression and the addition of PGE2 enhance DENV replication 39
3-6-5. DENV-2-elevated COX-2 expression and PGE2 production are required for DENV-2 replication 41
3-6-6. NS398 delays lethality from life-threatening DENV-2 infection in ICR suckling mice 44
3-6-7. DENV-2 elevates COX-2 promoter activation through mediation of NF-κB and C/EBP binding elements 45
3-6-8. NF-κB and MAPK/JNK-mediated C/EBP are responsible for DENV-2-induced COX-2 expression and viral replication 46
3-7. Prostasin impairs activation of epithelial growth factor receptor to suppress dengue virus propagation 48
3-7-1. Prostasin expression decreased in DENV-infected patients, mice, and hepatoma cell line 48
3-7-2. Postasin Overexpression decreases the mortality rate of DENV-infected ICR mice 49
3-7-3. Prostasin overexpression attenuates DENV propagation in Huh-7 cells 50
3-7-4. Prostasin overexpression suppresses DENV replication by reducing the COX-2 expression 51
3-7-5. Prostasin attenuates the EGFR-mediated COX-2 signaling pathway against DENV replication 52
3-7-6. Matriptase and HAI-2 regulate prostasin-mediated EGFR suppression to inhibit DENV replication 54
Chapter 4. Discussion 57
4-1. Alternative mechanism of BA on HCV replication 57
4-2. Alternative mechanism of lobohedleolide on HCV replication 57
4-3. The possible of BA and Lobohedleolide as a treatment against HCV 59
4-4. The importance and possible mechanism of COX-2 on DENV replication 60
4-5. The possible of COX-2 as a therapeutic target against DENV 60
4-6. The possible role of COX-2 in the pathogenesis of DHF 61
4-7. The possibility role of prostasin-mediated EGFR involved in DENV replication 62
Chapter 5. Conclusion 64
References 66
Figures catalogue
Figures and legends 80
Figure 1. The inhibition effect of betulinic acid (BA) on HCV replication. 80
Figure 2. Inhibitory effect of BA on HCV-induced COX-2 expression. 82
Figure 3. Restoration of HCV replication by exogenous COX-2 expression in BA-treated Ava5 cells. 84
Figure 4. Reduction effect of BA on HCV-induced NF-κB signaling pathway. 86
Figure 5. The reduction effect of BA on the phosphorylation of ERK1/2. 87
Figure 6. Proposed model of BA against HCV replication. 88
Figure 7. The suppression effect of BA, betulin and betulonic acid on DENV replication. 89
Figure 8. The inhibition effect of lobohedleolide on HCV replication. 90
Figure 9. Inhibition effect of lobohedleolide on HCV-induced COX-2 expression in protein and transcription levels. 92
Figure 10. Concentration-dependent restoration of HCV replication by exogenous COX-2 expression in lobohedleolide-treated Ava5 cells. 94
Figure 11. Effect of lobohedleolide on the transcriptional factor activity on COX-2 promoter. 95
Figure 12. Reduction effect of lobohedleolide on C/EBP transcription factor activity. 96
Figure 13. Mutagenized C/EBP on COX-2 promoter attenuated the inhibition effect of lobohedleolide on COX-2 promoter activity. 97
Figure 14. Reduction effect of lobohedleolide on C/EBP expression, c-Jun phosphorylation, and JNK phosphorylation. 98
Figure 15. Lobohedleolide did not affect the activation of NF-κB, ERK and p38. 99
Figure 16. Proposed model of lobohedleolide against HCV replication. 100
Figure 17. Lobohedleolide reduced DENV replication and protected ICR mice from life-threaten DENV infection. 101
Figure 18. AM-4 reduced HCV RNA replication by blocking viral entry. 103
Figure 19. AM-4 blocked HCV entry but not affect viral RNA replication and particle release. 105
Figure 20. Kinetic of inhibition of AM-4 on HCV entry. 107
Figure 21. AM-4 inhibited HCV cell-to-cell spread. 109
Figure 22. AM-4 did not affect the expression of HCV binding receptor. 111
Figure 23. Combination treatment of AM-4 with clinical used drugs additive reduced HCV replication. 112
Figure 24. Proposed model of AM-4 against HCV infection. 113
Figure 25. DENV induces COX-2 expression and PGE2 production in DF patients, DENV-infected mice, and human hepatoma cells. 114
Figure 26. DENV-2 induced COX-2 expression and PGE2 production in a concentration-dependent manner. 116
Figure 28. The growth curve of infectious DENV-2, and COX-2 overexpression and PGE2 addition induced DENV-2 propagation at early time point. 120
Figure 29. PGE2 did not affect the DENV-2 protease activity. 121
Figure 31. NS398 reduced DENV-2-elevated PGE2 production without cell cytotoxicity and DENV-2 propagation at early time point. 124
Figure 32. COX-2 expression is required for viral replication. 126
Figure 34. DENV-2 elevates COX-2 promoter activation through mediation of NF-κB and C/EBP binding elements. 130
Figure 35. NF-κB and MAPK/JNK-mediated C/EBP are responsible for DENV-2-induced COX-2 expression and viral replication. 132
Figure 36. MAPK/ERK and p38 are not responsible for DENV-2-induced COX-2 expression. 135
Figure 37. The inhibitors of MAPK/ERK and p38 did not suppress DENV-2 replication. 136
Figure 38. Proposed model to illustrate the mechanism of increased COX-2 expression and PGE2 production during DENV infection. 137
Figure 39. DENV infection decreases prostasin expression in DF patients, DENV-infected mice, and human hepatoma cells. 138
Figure 40. Prostasin overexpression protects mice from life-threatening DENV infection. 140
Figure 41. Prostatin overexpression decreases DENV replication and propagation. 142
Figure 42. Prostasin reduces DENV replication by decreasing COX-2 expression. 144
Figure 43. Prostasin knocks down EGFR to suppress DENV replication. 146
Figure 44. DENV replication requires the activation of Akt/COX-2 signaling. 148
Figure 45. C-Raf inhibitor did not reduce DENV-elevated COX-2 expression and DENV replication. 150
Figure 46. Prostasin-reduced EGFR expression is dependent on matriptase expression but is attenuated by HAI-2. 152
Figure 47. DENV infection and overexpression of HAI-2 facilitated the formation of prostasin-HAI-2 complex. 154
Figure 48. Model for the mechanism of prostasin-mediated EGFR expression against DENV-2 replication. 155
Table catalogue
Tables 156
Table1. The synergistic effect of BA when combined with various HCV inhibitors on the suppression of HCV RNA replication 156
Table2. The synergistic reduction effect of lobohedleolide with IFN-α, telaprevir, or sofosbuvir on HCV replication. 157
Appendix 158
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