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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王宗興 | zh_TW |
| dc.contributor.advisor | Tsung-Shing Andrew Wang | en |
| dc.contributor.author | 馬永賢 | zh_TW |
| dc.contributor.author | Wing Yin Timothy Ma | en |
| dc.date.accessioned | 2025-02-24T16:34:02Z | - |
| dc.date.available | 2026-03-01 | - |
| dc.date.copyright | 2025-02-24 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-02-13 | - |
| dc.identifier.citation | (1) Organization, W. H. WHO COVID-19 dashboard. 2025. https://data.who.int/dashboards/covid19/cases?n=c (accessed 2025 01/21).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96921 | - |
| dc.description.abstract | SARS-CoV-2 (嚴重急性呼吸道症候群冠狀病毒 2) 是一種 RNA 病毒，在過去幾年間造成 COVID-19 全球大流行。主蛋白酶 (Mpro)，又稱為 3CL 蛋白酶，是 SARS-CoV-2 基因組中一個有價值的藥物靶點，對其病毒複製至關重要。在本專案中，我們希望將已知的單功能肽醛抑制劑升級，加入額外的生物功能，如成像和降解，同時減少生物系統中醛的缺點。首先評估了 N 端或 C 端延伸，以加入可點選的炔烴把手進行官能化。對於 N 端延伸，保留了醛彈頭。在 C 端延伸時，則以不可逆共價丙烯酰胺或可逆共價氰基丙烯酰胺取代醛。透過銅(I)催化的疊氮烷基環加成 (CuAAC)，螢光團或 E3-連接酵素招引物可以附著在抑制劑上。我們成功合成了 N 端和 C 端降解結合物，這些結合物保留了與 Mpro 的抑制作用，有些化合物在轉染細胞模型中顯示出 Mpro 的標記或降解，同時也抑制了病毒感染。 | zh_TW |
| dc.description.abstract | SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, is the RNA virus that caused the COVID-19 global pandemic in the last few years. Main Protease (Mpro), also known as 3CL protease is a valuable drug target within the SARS-CoV-2 genome crucial for its viral replication. In this project, we would like to upgrade known monofunctional peptide aldehyde inhibitors to include extra biological functionalities, such as imaging and degradation, while reducing the drawbacks of aldehydes in biological systems. N- or C-terminal extension was first evaluated to include a clickable alkyne handle for functionalization. For N-terminal extension, the aldehyde warhead was retained. On the other hand, for C-terminal extensions, the aldehyde was replaced with irreversible covalent acrylamide or reversible covalent cyanoacrylamide moieties. Through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), fluorophores or E3-ligase recruiters can be attached to the inhibitor. We successfully synthesized N- and C-terminal degradation conjugates which retained their inhibition with Mpro, with some compounds showing labeling or degradation of Mpro in the transfection cell model, and also inhibition of viral infection. | en |
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| dc.description.provenance | Made available in DSpace on 2025-02-24T16:34:02Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii ABSTRACT iii CONTENTS iv LIST OF FIGURES vii LIST OF SCHEMES x LIST OF TABLES xii Abbreviations xiii Chapter 1 Introduction 1 1.1 COVID-19 and SARS-CoV-2 1 1.2 Main protease as a drug target 3 1.3 Mpro inhibitors 4 1.3.1 Mpro aldehyde inhibitors 5 1.3.2 Other Mpro inhibitors 7 1.4 Electrophilic warheads 8 1.4.1 Drawbacks of aldehydes in biological applications 8 1.4.2 Alternative warheads – acrylamides and cyanoacrylamides 10 1.5 Functionalization and conjugation of peptides and peptidomimetic molecules 12 1.6 Strategies for conjugation 13 1.7 Previous work on multifunctional conjugates for Mpro 14 1.7.1 Imaging 14 1.7.2 Targeted protein degradation 15 Chapter 2 Results and discussion 19 2.1 Molecular design 19 2.1.1 Design of Mpro-targeting bifunctional conjugates 19 2.1.2 Strategies for the installation of warheads at C-terminal 20 2.1.3 Utilization of click reaction for the assembly of conjugates 21 2.1.4 Design of N-terminal extended conjugates as control 23 2.2 Synthesis of MPI derivatives 23 2.2.1 Synthesis of MPI3 and MPI8 23 2.2.2 Synthesis of C-terminally modified derivatives 24 2.2.3 Synthesis of N-terminally modified derivatives 27 2.2.4 Synthesis of azide-containing functional units 28 2.3 Evaluation of Mpro inhibitors carrying various warheads 29 2.4 Evaluation of covalency and reversibility of warheads 32 2.5 Synthesis and evaluation of linkers’ effect on Mpro inhibitory activity 36 2.6 Synthesis of 8A-TAMRA (43) and imaging of Mpro in transfected cells 38 2.7 Synthesis of PROTAC molecules and evaluation of Mpro inhibitory activity of PROTACs 40 2.8 Evaluation of viral inhibition of compounds 44 2.9 Mpro degradation ability of PROTACs in transfected cells 46 Chapter 3 Conclusion and perspectives 50 Chapter 4 Materials and methods 51 4.1 General synthetic materials, methods, and instruments 51 4.2 Synthesis and characterization of compounds 53 4.2.1 Synthesis of MPI3 55 4.2.2 Synthesis of MPI8 58 4.2.3 Synthesis of MPI3-based derivatives 61 4.2.4 Synthesis of MPI8-based Derivatives 73 4.2.5 Synthesis of azide-containing E3-ligase recruiters 77 4.2.6 Synthesis of bifunctional conjugates 80 4.3 Biological assays 97 4.3.1 Cloning of enzyme-overexpressing plasmids 97 4.3.2 Recombinant overexpression and purification of Mpro 99 4.3.3 Main protease inhibition assay 100 4.3.4 Main protease covalent labeling assay 101 4.3.5 Main protease reversibility assay 102 4.3.6 Cell line and cell culture 102 4.3.7 AlamarBlue cell viability assay 102 4.3.8 Transfection of HEK293T cells with Mpro 103 4.3.9 Cellular imaging of Mpro 103 4.3.10 Mpro degradation assay in transfected HEK293T cells 104 4.3.11 Mpro degradation assay with competition and proteasome inhibition 105 4.3.12 Plaque reduction assay 105 References 106 Appendix 111 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 蛋白溶解-靶向嵌合體 (PROTAC) | zh_TW |
| dc.subject | 氰基丙烯酰胺 | zh_TW |
| dc.subject | 丙烯酰胺 | zh_TW |
| dc.subject | SARS-CoV-2 主要蛋白酶 | zh_TW |
| dc.subject | 成像探針 | zh_TW |
| dc.subject | 多功能結合物 | zh_TW |
| dc.subject | SARS-CoV-2 Main protease | en |
| dc.subject | imaging probes | en |
| dc.subject | proteolysis-targeting chimeras (PROTACs) | en |
| dc.subject | multifunctional conjugates | en |
| dc.subject | cyanoacrylamide | en |
| dc.subject | acrylamide | en |
| dc.title | 開發用於降解或成像 SARS-CoV-2 主要蛋白酶的抑制型雙功能結合物 | zh_TW |
| dc.title | Development of Inhibition-Based Bifunctional Conjugates for Degradation or Imaging of SARS-CoV-2 Main Protease | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 朱忠瀚;謝俊結 | zh_TW |
| dc.contributor.oralexamcommittee | John Chu;Jiun-Jie Shie | en |
| dc.subject.keyword | 多功能結合物,蛋白溶解-靶向嵌合體 (PROTAC),成像探針,SARS-CoV-2 主要蛋白酶,丙烯酰胺,氰基丙烯酰胺, | zh_TW |
| dc.subject.keyword | multifunctional conjugates,proteolysis-targeting chimeras (PROTACs),imaging probes,SARS-CoV-2 Main protease,acrylamide,cyanoacrylamide, | en |
| dc.relation.page | 159 | - |
| dc.identifier.doi | 10.6342/NTU202500655 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-02-14 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 化學系 | - |
| dc.date.embargo-lift | 2030-02-12 | - |
| 顯示於系所單位： | 化學系 | |
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