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研究生:項燕君
研究生(外文):Yen-Chun Shiang
論文名稱:以核酸適合體與金奈米粒子抑制凝血酶與第一型人類免疫缺陷病毒反轉錄酶活性
論文名稱(外文):Aptamer-Based Gold Nanoparticles for Inhibition of Thrombin and Human Immunodeficiency Virus Type 1 Reverse Transcriptase Activities
指導教授:張煥宗張煥宗引用關係
指導教授(外文):Huan-Tsung Chang
口試委員:胡焯淳吳立真黃志清林泱蔚
口試委員(外文):Cho-Chun HuLi-chen WuChih-Ching HuangYang-Wei Lin
口試日期:2013-07-12
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:151
中文關鍵詞:核酸適合體金奈米粒子凝血酶抗凝血劑第一型人類免疫缺陷病毒反轉錄酶
外文關鍵詞:aptamersgold nanoparticlesthrombinanticoagulanthuman immunodeficiency virus type 1 reverse transcriptase
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適合體是會形成特殊構形並且與特定分子有高親和力的單股寡核苷酸(oligonucleotide)。本論文主要探討表面修飾核酸適合體的金奈米粒子的製備,以及這些材料於調控酵素活性的應用。首先,將凝血酶核酸適合體以金–硫共價鍵結合到金奈米粒子表面,所製備出的金奈米複合物(TBA–Au NPs)能與凝血酶結合,進而抑制凝血酶與纖維蛋白原的反應,有效地延遲凝血的時間。抑制劑的活性可藉由改變金奈米粒子表面核酸適合體的密度調控,並且不受生物樣品中核酸酶的降解,能穩定存在於血漿中。以修飾有適合體互補序列的金奈米粒子做為解毒劑,能活化原先被抑制的凝血酶,凝血酶的活性可以藉由調控核酸適合體及其互補序列比例來調控。
在金奈米粒子表面修飾上一股互補用的序列(cDNA),利用寡核苷酸具有鹼基互補而形成雙股螺旋的特性,將凝血酶核酸適合體以非共價鍵的形式修飾於金奈米粒子表面(hTBA15/hTBA29/cDNA–Au NPs)。所設計的核酸適合體部分與這段互補用序列形成雙股核酸,這種利用氫鍵形成鹼基互補的鍵結讓核酸適合體與凝血酶之間有更好的作用力,金奈米粒子表面的核酸適合體彼此間磷酸根負電排斥效應減小,可提高核酸適合體抗凝血的效率。同時施加兩股不同的序列的凝血酶核酸適合體,分別和凝血酶不同的結合位置作用,使得奈米材料與凝血酶的結合能力提高,可在血漿中延長凝血酶凝血時間。
最後,表面修飾核酸適合體的金奈米粒子可以有效抑制第一型人類免疫缺陷病毒反轉錄酶的活性。為了有效的抑制病毒複製,利用兩股核酸適合體(Aptpol、AptRH)–分別與反轉錄酵素的聚合酶(polymerase)及核糖核酸內切酶(RNase H)結合–修飾在金奈米粒子表面來抑制病毒複製。所製備的金奈米複合物在核酸酶存在下仍能抑制反轉錄酵素,並可穩定存在於細胞中。以慢病毒(lentivirus)為載體進行病毒抑制實驗,被感染的細胞會製造出綠色螢光蛋白。隨著接有核酸適合體的金奈米複合物濃度越高,以流式細胞儀(flow cytometer)所偵測到的帶有綠色螢光蛋白的細胞數越少,可有效降低病毒感染率。


Aptamers are single-stranded oligonucleotides which form specific structure when bind to certain targets with high affinities. This thesis focuses on preparation and application of apatmer conjugated gold nanoparticles (Au NPs, 13-nm in diameter) for enzyme activities modulation. First, thrombin-binding-aptamer conjugated gold nanoparticles (TBA–Au NPs) for highly effective control of thrombin activity towards fibrinogen. A 29-base long oligonucleotide (TBA29), has known no enzymatic inhibitory functions for thrombin-mediated coagulation, however, has been demonstrated an ultra-high anticoagulant potency of TBA29–Au NPs via the steric blocking effect, with two orders of magnitude higher than that of free TBA29.
Second, The hTBA15/hTBA29/cDNA–Au NPs exhibit high anticoagulant activity as a result of inhibiting the thrombin-mediated cleavage of fibrinogen. Instead of directly conjugating functional aptamers onto Au NP surfaces through Au–S bonding, in this study hTBA15 and hTBA29 were hybridized with a complementary sequences that were themselves covalently bound to the Au NPs. The hTBA15/hTBA29/cDNA–Au NPs exert their high inhibitory effect toward thrombin through a combination of multivalent interactions and steric blocking effects.
Finally, aptamer-conjugated gold nanoparticles (Apt–Au NPs) as highly effective inhibitors for human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT). Two Apts, RT1t49 (Aptpol) and ODN 93 (AptRH), which recognized to polymerase and RNase H regions of HIV-1 RT, are used to conjugate Au NPs to prepare Aptpol–Au NPs and AptRH–Au NPs, respectively. A HIV-lentiviral vector-based antiviral assay has been applied to determine the inhibitory effect of aptamers or Apt–Au NPs on the early stages of their replication cycle. The nuclease-stable G-quadruplex structure of 40AptRH-T45–Au NPs show inhibitory efficiency in the retroviral replication cycle with a decreasing infectivity.


Contents Page
中文摘要 I
關鍵詞 I
Abstract II
Keywords III
Table Contents VII
Figure Contents VIII
Conclusions and Prospects 146
Publications 149
Conferences 151

1 Introduction 1
1.1 Aptamer 2
1.1.1 Selection of Aptamers 2
1.1.2 Advantages of Aptamer 3
1.1.3 Applications 4
1.1.3.1 Biosensors 4
1.1.3.2 Diagnostics and Therapeutics 8
1.2 Thrombin 11
1.2.1 Role of Thrombin in Clotting Cascade 11
1.2.2 Anticoagulant Drugs 12
1.2.3 Aptamer-Based Anticoagulation 13
1.3 Reverse Transcriptase of Type 1 Human Immunodeficiency Virus 20
1.3.1 Functions of Reverse Transcriptase in Replication Cycle of Human Immunodeficiency Virus 20
1.3.2 Antiretroviral Medications and Treatments 21
1.3.3 Aptamer-Based Anti-HIV Therapy 23
1.3.4 Nanomaterial-Based Anti-HIV Therapy 29
1.4 Motive of Research 32
1.5 References 34

2 Aptamer-Conjugated Nanoparticles Efficiently Control the Activity of Thrombin 54
2.1 Introduction 55
2.2 Experimental Section 55
2.2.1 Chemicals 55
2.2.2 Synthesis of Gold Nanoparticles 56
2.2.3 Preparation of TBA–Au NPs 57
2.2.4 Real-Time Kinetics of Coagulation 57
2.2.5 Enzymatic Activity Assays 58
2.2.6 Binding Constants of the TBA–Au NPs with Thrombin 58
2.2.7 Stability of TBA29–Au NPs 59
2.2.8 Antidote Reaction Using cTBA and cTBA–Au NPs 60
2.2.9 PT and aPTT Tests 60
2.3 Results and Discussion 61
2.3.1 Design of TBA–Au NPs 61
2.3.2 Extensions of TBA-Au NPs 63
2.3.3 Ligand Density of TBA–Au NPs 65
2.3.4 Stability of TBA–Au NPs 66
2.3.5 The Antidote Effect of cTBA29–Au NPs 66
2.3.6 Elongation of PT and aPPT by 100TBA29–Au NPs 67
2.4 Conclusions 68
2.5 References 69

3 Gold Nanoparticles Presenting Hybridized Self-Assembled Aptamers Exhibit Enhanced Inhibition of Thrombin 85
3.1 Introduction 86
3.2 Experimental Section 88
3.2.1 Chemicals 88
3.2.2 Preparation of cDNA–Au NPs 88
3.2.3 Preparation of hTBA/cDNA–Au NPs 89
3.2.4 Real-Time Kinetics of Coagulation 90
3.2.5 Enzymatic Activity Assays 90
3.2.6 TCT and Whole Blood CT Tests 90
3.2.7 PT and aPTT Tests 91
3.2.8 Antidote Reactions Using AD-hTBA and AD-hTBA–Au NPs 92
3.3 Results and Discussion 92
3.3.1 Anticoagulation of hTBA/cDNA–Au NPs 92
3.3.2 Density of hTBAs 95
3.3.3 Human Plasma and Whole Blood Assays 96
3.3.4 Reversible Binding Reaction of the Antidote 97
3.4 Conclusions 98
3.5 References 100

4 Highly Efficient Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase by Aptamers Functionalized Gold Nanoparticles 115
4.1 Introduction 116
4.2 Experimental Section 117
4.2.1 Chemicals 117
4.2.2 Preparation of Apt–Au NPs 118
4.2.3 HIV-1 RT Activity Assay 119
4.2.4 Inhibition of RT Enzymatic Activity 120
4.2.5 Stability of Apt–Au NPs 120
4.2.6 Synergistic Assay 121
4.2.7 Generation of Lentivirus 121
4.2.8 Cytotoxicity Assay 122
4.2.9 Antiviral Assay 123
4.3 Results and Discussion 123
4.3.1 Apt–Au NPs as HIV-1 RT Inhibitor 123
4.3.2 Effect of Ligand Density and Linker Length 125
4.3.3 Stability of Aptamer and Apt–Au NPs 126
4.3.4 Synergistic Effect 127
4.3.5 Inhibition of Lentivirus Infectivity 128
4.3.6 Comparison with Commercial anti-HIV Drug 129
4.4 Conclusions 129
4.5 References 131


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