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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 朱忠瀚 | zh_TW |
| dc.contributor.advisor | John Chu | en |
| dc.contributor.author | 鍾學緯 | zh_TW |
| dc.contributor.author | Hsueh-Wei Chung | en |
| dc.date.accessioned | 2025-02-13T16:26:56Z | - |
| dc.date.available | 2025-02-14 | - |
| dc.date.copyright | 2025-02-13 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-02-05 | - |
| dc.identifier.citation | 1.Chen, M.; Wang, S.; Yu, X. Cryptand-imidazolium Supported Total Synthesis of the Lasso Peptide BI-32169 and Its D-Enantiomer. Chem. Commun. 2019, 55 (23), 3323–3326.
2.Braffman, N. R.; Piscotta, F. J.; Hauver, J.; Campbell, E. A.; Link, A. J.; Darst, S. A. Structural Mechanism of Transcription Inhibition by Lasso Peptides Microcin J25 and Capistruin. Proc. Natl. Acad. Sci. 2019, 116 (4), 1273–1278. 3.Vrettos, E. I.; Sayyad, N.; Mavrogiannaki, E. M.; Stylos, E.; Kostagianni, A. D.; Papas, S.; Mavromoustakos, T.; Theodorou, V.; Tzakos, A. G. Unveiling and Tackling Guanidinium Peptide Coupling Reagent Side Reactions Towards the Development of Peptide–Drug Conjugates. RSC Adv. 2017, 7 (80), 50519–50526. 4.Cheng, C.; Hua, Z.-C. Lasso Peptides: Heterologous Production and Potential Medical Application. Front. Bioeng. Biotechnol. 2020, 8, 239. 5.Salomón, R. A.; Farías, R. N. Microcin 25, a Novel Antimicrobial Peptide Produced by Escherichia coli. J. Bacteriol. 1992, 174 (22), 7428–7435. 6.Blond, A.; Cheminant, M.; Destoumieux-Garzón, D.; Ségalas-Milazzo, I.; Peduzzi, J.; Goulard, C.; Rebuffat, S. Thermolysin-Linearized Microcin J25 Retains the Structured Core of the Native Macrocyclic Peptide and Displays Antimicrobial Activity. Eur. J. Biochem. 2002, 269 (24), 6212–6222. 7.Weber, W.; Fischli, W.; Hochuli, E.; Kupfer, E.; Weibel, E. K. Anantin—a Peptide Antagonist of the Atrial Natriuretic Factor (ANF). I. Producing Organism, Fermentation, Isolation, and Biological Activity. J. Antibiot. 1991, 44 (2), 164–171. 8.Salomón, R. A.; Farías, R. N. The FhuA Protein Is Involved in Microcin 25 Uptake. J. Bacteriol. 1993, 175 (23), 7741–7742. 9.Salomón, R. A.; Farías, R. N. The Peptide Antibiotic Microcin 25 Is Imported through the TonB Pathway and the SbmA Protein. J. Bacteriol. 1995, 177 (11), 3323–3325. 10.Yuzenkova, J.; Delgado, M.; Nechaev, S.; Savalia, D.; Epshtein, V.; Artsimovitch, I.; Mooney, R. A.; Landick, R.; Farias, R. N.; Salomón, R.; Severinov, K. Mutations of Bacterial RNA Polymerase Leading to Resistance to Microcin J25. J. Biol. Chem. 2002, 277 (52), 50867–50875. 11.Solbiati, J. O.; Ciaccio, M.; Farías, R. N.; González-Pastor, J. E.; Moreno, F.; Salomón, R. A. Sequence Analysis of the Four Plasmid Genes Required to Produce the Circular Peptide Antibiotic Microcin J25. J. Bacteriol. 1999, 181 (8), 2659–2662. 12.Solbiati, J. O.; Ciaccio, M.; Farías, R. N.; Salomón, R. A. Genetic Analysis of Plasmid Determinants for Microcin J25 Production and Immunity. J. Bacteriol. 1996, 178 (12), 3661–3663. 13.Destoumieux-Garzón, D.; Duquesne, S.; Peduzzi, J.; Goulard, C.; Desmadril, M.; Letellier, L.; Rebuffat, S.; Boulanger, P. The Iron-Siderophore Transporter FhuA Is the Receptor for the Antimicrobial Peptide Microcin J25: Role of the Microcin Val11-Pro16 β-Hairpin Region in the Recognition Mechanism. Biochem. J. 2005, 389 (Pt 3), 869–876. 14.Bellomio, A.; Vincent, P. A.; de Arcuri, B. F.; Salomón, R. A.; Morero, R. D.; Farías, R. N. The Microcin J25 β-Hairpin Region Is Important for Antibiotic Uptake but Not for RNA Polymerase and Respiration Inhibition. Biochem. Biophys. Res. Commun. 2004, 325 (4), 1454–1458. 15.Merrifield, R. B. Solid-Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 1963, 85 (14), 2149–2154. 16.Mazaheri Tehrani, M.; Erfani, M.; Amirmozafari, N.; Nejadsattari, T. Synthesis of a Peptide Derivative of Microcin J25 and Evaluation of Antibacterial and Biological Activities. Iran. J. Pharm. Res. 2019, 18 (3), 1264–1276. 17.Cornelis, R.; Nordberg, M. Chapter 2 - General Chemistry, Sampling, Analytical Methods, and Speciation. In Handbook on the Toxicology of Metals, 3rd ed.; Nordberg, G. F.; Fowler, B. A.; Nordberg, M.; Friberg, L. T., Eds.; Academic Press: Burlington, 2007; pp 11–38. 18.Aureliano, M.; Gumerova, N.; Rompel, A. The Biological Applications of Metals and Metal Complexes. Metals 2023, 13, 1041. 19.Karges, J.; Stokes, R. W.; Cohen, S. M. Metal Complexes for Therapeutic Applications. Trends Chem. 2021, 3 (7), 523–534. 20.Frei, A.; Zuegg, J.; Elliott, A. G.; Baker, M.; Braese, S.; Brown, C.; Chen, F.; C, G. D.; Dujardin, G.; Jung, N.; King, A. P.; Mansour, A. M.; Massi, M.; Moat, J.; Mohamed, H. A.; Renfrew, A. K.; Rutledge, P. J.; Sadler, P. J.; Todd, M. H.; Willans, C. E.; Wilson, J. J.; Cooper, M. A.; Blaskovich, M. A. T. Metal Complexes as a Promising Source for New Antibiotics. Chem. Sci. 2020, 11 (10), 2627–2639. 21.Wang, Z.; Li, J.; Lin, G.; He, Z.; Wang, Y. Metal Complex-Based Liposomes: Applications and Prospects in Cancer Diagnostics and Therapeutics. J. Control. Release 2022, 348, 1066–1088. 22.Kilpin, K. J.; Dyson, P. J. Enzyme Inhibition by Metal Complexes: Concepts, Strategies, and Applications. Chem. Sci. 2013, 4 (4), 1410–1419. 23.Lehn, J.-M. Supramolecular Chemistry—Scope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1988, 27 (1), 89–112. 24.Pedersen, C. J. The Discovery of Crown Ethers (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1988, 27 (8), 1021–1027. 25.Cram, D. J. The Design of Molecular Hosts, Guests, and Their Complexes (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1988, 27 (8), 1009–1020. 26.Design, Synthesis, Action! Molecular Machines Take the 2016 Nobel Prize in Chemistry. ACS Cent. Sci. 2016, 2 (10), 674–675. 27.Hewitt, S. H.; Wilson, A. J. Metal Complexes as "Protein Surface Mimetics". Chem. Commun. 2016, 52 (63), 9745–9756. 28.Desbouis, D.; Troitsky, I. P.; Belousoff, M. J.; Spiccia, L.; Graham, B. Copper(II), Zinc(II), and Nickel(II) Complexes as Nuclease Mimetics. Coord. Chem. Rev. 2012, 256 (11), 897–937. 29.Melchior, M.; Thompson, K. H.; Jong, J. M.; Rettig, S. J.; Shuter, E.; Yuen, V. G.; Zhou, Y.; McNeill, J. H.; Orvig, C. Vanadium Complexes as Insulin Mimetic Agents: Coordination Chemistry and In Vivo Studies of Oxovanadium(IV) and Dioxovanadate(V) Complexes Formed from Naturally Occurring Chelating Oxazolinate, Thiazolinate, or Picolinate Units. Inorg. Chem. 1999, 38 (10), 2288–2293. 30.Wang, L.; Wang, N.; Zhang, W.; Cheng, X.; Yan, Z.; Shao, G.; Wang, X.; Wang, R.; Fu, C. Therapeutic Peptides: Current Applications and Future Directions. Signal Transduct. Target. Ther. 2022, 7 (1), 48. 31.Craik, D. J.; Fairlie, D. P.; Liras, S.; Price, D. The Future of Peptide-Based Drugs. Chem. Biol. Drug Des. 2013, 81 (1), 136–147. 32.Kamenik, A. S.; Lessel, U.; Fuchs, J. E.; Fox, T.; Liedl, K. R. Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization. J. Chem. Inf. Model. 2018, 58 (5), 982–992. 33.Sindhikara, D.; Spronk, S. A.; Day, T.; Borrelli, K.; Cheney, D. L.; Posy, S. L. Improving Accuracy, Diversity, and Speed with Prime Macrocycle Conformational Sampling. J. Chem. Inf. Model. 2017, 57 (8), 1881–1894. 34.Komar, A. A. Molecular Peptide Grafting as a Tool to Create Novel Protein Therapeutics. Molecules 2023, 28 (5), 2383. 35.Zhang, L.; Wang, J.; Xu, A.; Zhong, C.; Lu, W.; Deng, L.; Li, R. A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice. PLoS One 2016, 11 (9), e0163080. 36.Mihara, E.; Watanabe, S.; Bashiruddin, N. K.; Nakamura, N.; Matoba, K.; Sano, Y.; Maini, R.; Yin, Y.; Sakai, K.; Arimori, T.; Matsumoto, K.; Suga, H.; Takagi, J. Lasso-Grafting of Macrocyclic Peptide Pharmacophores Yields Multi-Functional Proteins. Nat. Commun. 2021, 12 (1), 1543. 37.González-Castro, R.; Gómez-Lim, M. A.; Plisson, F. Cysteine-Rich Peptides: Hyperstable Scaffolds for Protein Engineering. ChemBioChem 2021, 22 (6), 961–973. 38.Gunasekera, S.; Foley, F. M.; Clark, R. J.; Sando, L.; Fabri, L. J.; Craik, D. J.; Daly, N. L. Engineering Stabilized Vascular Endothelial Growth Factor-A Antagonists: Synthesis, Structural Characterization, and Bioactivity of Grafted Analogues of Cyclotides. J. Med. Chem. 2008, 51 (24), 7697–7704. 39.Saito, F.; Bode, J. W. Synthesis and Stabilities of Peptide-Based [1]Rotaxanes: Molecular Grafting onto Lasso Peptide Scaffolds. Chem. Sci. 2017, 8 (4), 2878–2884. 40.Hegemann, J. D.; De Simone, M.; Zimmermann, M.; Knappe, T. A.; Xie, X.; Di Leva, F. S.; Marinelli, L.; Novellino, E.; Zahler, S.; Kessler, H.; Marahiel, M. A. Rational Improvement of the Affinity and Selectivity of Integrin Binding of Grafted Lasso Peptides. J. Med. Chem. 2014, 57 (13), 5829–5834. 41.Baquero, F.; Beis, K.; Craik, D. J.; Li, Y.; Link, A. J.; Rebuffat, S.; Salomón, R.; Severinov, K.; Zirah, S.; Hegemann, J. D., The pearl jubilee of microcin J25: thirty years of research on an exceptional lasso peptide. Nat. Prod. Rep. 2024, 41 (3), 469–511. 42.Pavlova, O.; Mukhopadhyay, J.; Sineva, E.; Ebright, R. H.; Severinov, K., Systematic structure-activity analysis of microcin J25. J. Biol. Chem. 2008, 283 (37), 25589–25595. 43.Piscotta, F. J.; Tharp, J. M.; Liu, W. R.; Link, A. J., Expanding the chemical diversity of lasso peptide MccJ25 with genetically encoded noncanonical amino acids. Chem. Commun. 2015, 51 (2), 409–412. 44.Malik, I. T.; Hegemann, J. D.; Brötz-Oesterhelt, H., Generation of Lasso Peptide-Based ClpP Binders. Int. J. Mol. Sci. 2022, Online. 45.Long, T.; Liu, L.; Tao, Y.; Zhang, W.; Quan, J.; Zheng, J.; Hegemann, J. D.; Uesugi, M.; Yao, W.; Tian, H.; Wang, H., Light-Controlled Tyrosine Nitration of Proteins. Angew. Chem. Int. Ed. 2021, 60 (24), 13414–13422. 46.Bellomio, A.; Rintoul, M. A. R.; Morero, R. D., Chemical modification of microcin J25 with diethylpyrocarbonate and carbodiimide: evidence for essential histidyl and carboxyl residues. Biochem. Biophys. Res. Commun. 2003, 303 (2), 458–462. 47.Soudy, R.; Etayash, H.; Bahadorani, K.; Lavasanifar, A.; Kaur, K., Breast Cancer Targeting Peptide Binds Keratin 1: A New Molecular Marker for Targeted Drug Delivery to Breast Cancer. Mol. Pharmaceutics 2017, 14 (3), 593–604. 48.Yu, H.; Ma, Z.; Meng, S.; Qiao, S.; Zeng, X.; Tong, Z.; Jeong, K. C., A novel nanohybrid antimicrobial based on chitosan nanoparticles and antimicrobial peptide microcin J25 with low toxicity. Carbohydr. Polym. 2021, 253, 117309. 49.Mohri, K.; Nhat, K. P. H.; Zouda, M.; Warashina, S.; Wada, Y.; Watanabe, Y.; Tagami, S.; Mukai, H., Lasso peptide microcin J25 variant containing RGD motif as a PET probe for integrin αvβ3 in tumor imaging. Eur. J. Pharm. Sci. 2023, 180, 106339. 50.Schröder, H. V.; Zhang, Y.; Link, A. J., Dynamic covalent self-assembly of mechanically interlocked molecules solely made from peptides. Nat. Chem. 2021, 13 (9), 850–857. 51.Naimi, S.; Zirah, S.; Hammami, R.; Fernandez, B.; Rebuffat, S.; Fliss, I., Fate and Biological Activity of the Antimicrobial Lasso Peptide Microcin J25 Under Gastrointestinal Tract Conditions. Front. Microbiol. 2018, 9, Article 1030. 52.Ritter, S. C.; Yang, M. L.; Kaznessis, Y. N.; Hackel, B. J., Multispecies activity screening of microcin J25 mutants yields antimicrobials with increased specificity toward pathogenic Salmonella species relative to human commensal Escherichia coli. Biotechnol. Bioeng. 2018, 115 (10), 2394–2404. 53.Yu, H.; Li, N.; Zeng, X.; Liu, L.; Wang, Y.; Wang, G.; Cai, S.; Huang, S.; Ding, X.; Song, Q.; Qiao, S., A Comprehensive Antimicrobial Activity Evaluation of the Recombinant Microcin J25 Against the Foodborne Pathogens Salmonella and E. coli O157:H7 by Using a Matrix of Conditions. Front. Microbiol. 2019, 10, Article 1112. 54.Blond, A.; Péduzzi, J.; Goulard, C.; Chiuchiolo, M. J.; Barthélémy, M.; Prigent, Y.; Salomón, R. A.; Farías, R. N.; Moreno, F.; Rebuffat, S., The cyclic structure of microcin J25, a 21-residue peptide antibiotic from Escherichia coli. Eur. J. Biochem. 1999, 259 (3), 747–755. 55.Kotova, O.; Blasco, S.; Twamley, B.; O'Brien, J.; Peacock, R. D.; Kitchen, J. A.; Martínez-Calvo, M.; Gunnlaugsson, T., The application of chiroptical spectroscopy (circular dichroism) in quantifying binding events in lanthanide directed synthesis of chiral luminescent self-assembly structures. Chem. Sci. 2015, 6 (1), 457–471. 56.Grimm, S. H.; Gagestein, B.; Keijzer, J. F.; Liu, N.; Wijdeven, R. H.; Lenselink, E. B.; Tuin, A. W.; van den Nieuwendijk, A. M. C. H.; van Westen, G. J. P.; van Boeckel, C. A. A.; Overkleeft, H. S.; Neefjes, J.; van der Stelt, M., Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors. Bioorg. Med. Chem. 2019, 27 (5), 692–699. 57.Zhang, J.; Frankevich, V.; Knochenmuss, R.; Friess, S. D.; Zenobi, R., Reduction of Cu(II) in matrix-assisted laser desorption/ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 2003, 14 (1), 42–50. 58.Hegemann, J. D., Combined thermal and carboxypeptidase Y stability assays for probing the threaded fold of lasso peptides. Methods Enzymol. 2022, 663, 177–204. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96433 | - |
| dc.description.abstract | 套索胜肽(lasso peptide)，是一系列如套索一般構型的特殊胜肽家族。由於其結構的特殊性，該種類的胜肽對於溫度、酸鹼度、酵素等環境因素皆具有極高的穩定性，然而此結構亦阻礙了科學家們對套索胜肽進行詳細的研究以及開發泛用的合成方法。在本研究中，我們將利用兩種方式來探索microcinJ25 (MccJ25)—一個標誌性的套索胜肽—的化學空間: 一、結合金屬鍵結(metal coordinate)、固相胜肽合成法(solid phase peptide synthesis, SPPS)及有機化學合成仿生構型；二、結合酵素剪切以及化學修飾的方式對現有的MccJ25構型進行修改。
在方法一中，我們設計了數個模仿套索胜肽，並且可經由化學合成得到的仿生分子 (mimic)。我的論文主要著重在金屬仿生分子 (M-mimic) 的合成，其中含有數個可與金屬鍵結的天然及非天然胺基酸，例如組胺酸及2,6-吡啶二甲酸。我們假設當這些分子被放置於空間中適當的位置時，這些雜環將與中心金屬產生配位鍵結並形成金屬錯合物 (metal complexes)。 在方法二中，我們經由篩選一系列的酵素後，發現嗜熱菌蛋白酶 (Thermolysin) 可在特定位點上，將MccJ25分子從[1]輪烷轉變成[2]輪烷。利用此特性，我們嘗試探索修飾該分子骨架的方式。例如，將有機小分子放入此[2]輪烷的骨架。這項如手術般精確的酵素-化學修飾的手法將使我們得以更加深入地探索及利用套索胜肽。 | zh_TW |
| dc.description.abstract | Lasso peptides are a peptide family with a lariat-like 3D structure. Due to its unique threaded structure, lasso peptides are stable to heat, pH, enzyme digestions, and other kinds of environmental stress. However, the same unique structure has also hindered their detailed characterization and prevented the development of generalized synthetic methods. In this study, we aimed to explore the chemical landscape of microcin J25, the prototypical lasso peptide, by two approaches: 1) synthesize structural mimics of MccJ25 by combining solid phase peptide synthesis and organic synthesis, and 2) engineer the existing MccJ25 scaffold by combining enzymatic cleavage and chemical modifications.
In the first approach, we proposed designs that are synthetically accessible to mimic the structure of a threaded peptide. My thesis focuses on the M-mimic, which includes natural and non-natural amino acids, such as histidine and 2,6-pyridinedicarboxylic acid. We hypothesized that if these residues are positioned in the appropriation positions within the peptide, their heterocycles may function as ligands to coordinate a central metal cation and form a complex that imitates the shape of MccJ25. In the second approach, we identified thermolysin from screening a collection of proteases6, and it cleaves MccJ25 site-specifically to convert it from a [1]rotaxane to a [2]rotaxane. We are currently exploring the possibility of modifying this scaffold further. For example, various small molecules can be installed by organic synthesis into the [2]rotaxane. Such a precise chemoenzymatic manipulation is akin to a surgical incision-and-repair process and enabled us to expand the functional group repertoire of lasso peptides. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-02-13T16:26:56Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-02-13T16:26:56Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 摘要 iii Abstract iv 目次 v List of Figures vii List of Schemes ix List of Tables ix Chapter 1. Introduction 1 1.1 General 1 1.1.1 Lasso peptide 1 1.1.2 MccJ25 2 1.1.3 Structural analysis 4 1.2 Synthetic mimic 5 1.2.1 SPPS 5 1.2.2 Lasso peptide total synthesis 6 1.2.3 Metal complex 7 1.3 MccJ25 scaffold 7 1.3.1 Peptide ligand scaffold 7 1.3.2 MccJ25 variant research 8 1.3.3 Enzyme cleavage research 10 Chapter 2. Results & Discussions 12 2.1 M-mimic 12 2.1.1 Molecular design and specific aim 12 2.1.2 Synthesis of building blocks 13 2.1.3 Pre-M mimic synthesis 13 2.1.4 Pre-M-Cu2+ bioactivity 19 2.1.5 M-mimic synthesis 21 2.2 MccJ25 surgery 31 2.2.1 Molecular design and specific aim 31 2.2.2 Enzyme cleavage and characterization 32 2.2.3 On-resin MccJ25 surgery 35 2.2.4 Chemically modified MccJ25 39 2.2.5 Characterization of [v11] 42 2.2.6 Bioactivity 44 Chapter 3. Conclusion 46 Chapter 4. Experimental Section 48 Reference 78 Appendix 86 | - |
| dc.language.iso | en | - |
| dc.subject | 微菌素J25 | zh_TW |
| dc.subject | MccJ25修飾 | zh_TW |
| dc.subject | 胜肽骨架 | zh_TW |
| dc.subject | 固相胜肽合成 | zh_TW |
| dc.subject | 金屬錯合物 | zh_TW |
| dc.subject | 套索胜肽 | zh_TW |
| dc.subject | SPPS | en |
| dc.subject | metal complex | en |
| dc.subject | MccJ25 | en |
| dc.subject | lasso peptide | en |
| dc.subject | MccJ25 engineer | en |
| dc.subject | peptide grafting | en |
| dc.title | MccJ25的酵素修飾及仿生分子合成 | zh_TW |
| dc.title | Synthetic Mimics and Enzymatic Modifications of MccJ25 | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 張晉源;王書品 | zh_TW |
| dc.contributor.oralexamcommittee | Chin-Yuan Chang;Shu-Ping Wang | en |
| dc.subject.keyword | 套索胜肽,微菌素J25,金屬錯合物,固相胜肽合成,胜肽骨架,MccJ25修飾, | zh_TW |
| dc.subject.keyword | lasso peptide,MccJ25,metal complex,SPPS,peptide grafting,MccJ25 engineer, | en |
| dc.relation.page | 116 | - |
| dc.identifier.doi | 10.6342/NTU202500331 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-02-05 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 化學系 | - |
| dc.date.embargo-lift | 2025-02-14 | - |
| 顯示於系所單位： | 化學系 | |
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