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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁碧惠 | zh_TW |
| dc.contributor.advisor | Pi-Hui Liang | en |
| dc.contributor.author | 張振卓 | zh_TW |
| dc.contributor.author | ZHEN-ZHUO TEO | en |
| dc.date.accessioned | 2021-07-11T15:25:49Z | - |
| dc.date.available | 2024-08-17 | - |
| dc.date.copyright | 2019-03-11 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
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J.; DiStefano, P. S.; Bertin, J.; Sansonetti, P. J.; Philpott, D. J. Nod1 Detects a Unique Muropeptide from Gram-Negative Bacterial Peptidoglycan. Science 2003, 300, 1584-1587. 13. Strober, W.; Murray, P. J.; Kitani, A.; Watanabe, T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat. Rev. Immunol. 2005, 6, 9. 14. Geddes, K.; Magalhães, J. G.; Girardin, S. E. Unleashing the therapeutic potential of NOD-like receptors. Nat. Rev. Drug Discovery 2009, 8, 465. 15. Chamaillard, M.; Hashimoto, M.; Horie, Y.; Masumoto, J.; Qiu, S.; Saab, L.; Ogura, Y.; Kawasaki, A.; Fukase, K.; Kusumoto, S.; Valvano, M. A.; Foster, S. J.; Mak, T. W.; Nuñez, G.; Inohara, N. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat. Immunol. 2003, 4, 702. 16. Inohara, N.; Ogura, Y.; Fontalba, A.; Gutierrez, O.; Pons, F.; Crespo, J.; Fukase, K.; Inamura, S.; Kusumoto, S.; Hashimoto, M.; Foster, S. J.; Moran, A. P.; Fernandez-Luna, J. L.; Nuñez, G. Host Recognition of Bacterial Muramyl Dipeptide Mediated through NOD2: IMPLICATIONS FOR CROHN′S DISEASE. J. Biol. Chem. 2003, 278, 5509-5512. 17. Grimes, C. L.; Ariyananda, L. D. Z.; Melnyk, J. E.; O’Shea, E. K. The Innate Immune Protein Nod2 Binds Directly to MDP, a Bacterial Cell Wall Fragment. J. Am. Chem. Soc. 2012, 134, 13535-13537. 18. Grimes, C. L.; Podolsky, D. K.; O’Shea, E. K. Synthesis of biologically active biotinylated muramyl dipeptides. Bioorganic Med. Chem. Lett. 2010, 20, 6061-6063. 19. Girardin, S. E.; Boneca, I. G.; Viala, J.; Chamaillard, M.; Labigne, A.; Thomas, G.; Philpott, D. J.; Sansonetti, P. J. Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection. J. Biol. Chem. 2003, 278, 8869-8872. 20. Maekawa, S.; Ohto, U.; Shibata, T.; Miyake, K.; Shimizu, T. Crystal structure of NOD2 and its implications in human disease. Nat. Commun. 2016, 7, 11813. 21. Jakopin, Ž. Nucleotide-Binding Oligomerization Domain (NOD) Inhibitors: A Rational Approach toward Inhibition of NOD Signaling Pathway. J. Med. Chem 2014, 57, 6897-6918. 22. Philpott, D. J.; Sorbara, M. T.; Robertson, S. J.; Croitoru, K.; Girardin, S. E. NOD proteins: regulators of inflammation in health and disease. Nat. Rev. Immunol. 2013, 14, 9. 23. Murray, P. J. Beyond peptidoglycan for Nod2. Nat. Immunol. 2009, 10, 1053. 24. Pashenkov, M. V.; Dagil, Y. A.; Pinegin, B. V. NOD1 and NOD2: Molecular targets in prevention and treatment of infectious diseases. Int. Immunopharmacol. 2018, 54, 385-400. 25. Meyers, P. A.; Schwartz, C. L.; Krailo, M. D.; Healey, J. H.; Bernstein, M. L.; Betcher, D.; Ferguson, W. S.; Gebhardt, M. C.; Goorin, A. M.; Harris, M.; Kleinerman, E.; Link, M. P.; Nadel, H.; Nieder, M.; Siegal, G. P.; Weiner, M. A.; Wells, R. J.; Womer, R. B.; Grier, H. E. Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall Survival—A Report From the Children's Oncology Group. J. Clin. Oncol. 2008, 26, 633-638. 26. Kager, L.; Pötschger, U.; Bielack, S. Review of mifamurtide in the treatment of patients with osteosarcoma. Ther. Clin. Risk. Manag. 2010, 6, 279-286. 27. Frampton, J. E. Mifamurtide. Paediatr. Drugs 2010, 12, 141-153. 28. Ichiro, A. Review: Inducer of cytokines in vivo: Overview of field and romurtide experience. Int. J. Immunopharmacol 1992, 14, 487-496. 29. Namba, K.; Nakajima, R.; Otani, T.; Azuma, I. Oral application of romurtide, a synthetic muramyl dipeptide derivative, stimulates nonspecific resistance to microbial infections and hematopoiesis in mice. Vaccine 1996, 14, 1149-1153. 30. Melnyk, J. E.; Mohanan, V.; Schaefer, A. K.; Hou, C.-W.; Grimes, C. L. Peptidoglycan Modifications Tune the Stability and Function of the Innate Immune Receptor Nod2. J. Am. Chem. Soc. 2015, 137, 6987-6990. 31. Rubino, S. J.; Magalhaes, J. G.; Philpott, D.; Bahr, G. M.; Blanot, D.; Girardin, S. E. Identification of a synthetic muramyl peptide derivative with enhanced Nod2 stimulatory capacity. Innate Immun. 2013, 19, 493-503. 32. Jakopin, Ž.; Gobec, M.; Mlinarič-Raščan, I.; Sollner Dolenc, M. Immunomodulatory Properties of Novel Nucleotide Oligomerization Domain 2 (Nod2) Agonistic Desmuramyldipeptides. J. Med. Chem. 2012, 55, 6478-6488. 33. Gobec, M.; Mlinarič-Raščan, I.; Dolenc, M. S.; Jakopin, Ž. Structural requirements of acylated Gly-l-Ala-d-Glu analogs for activation of the innate immune receptor NOD2. Eur. J. Med. Chem. 2016, 116, 1-12. 34. Gobec, M.; Tomašič, T.; Štimac, A.; Frkanec, R.; Trontelj, J.; Anderluh, M.; Mlinarič-Raščan, I.; Jakopin, Ž. Discovery of Nanomolar Desmuramylpeptide Agonists of the Innate Immune Receptor Nucleotide-Binding Oligomerization Domain-Containing Protein 2 (NOD2) Possessing Immunostimulatory Properties. Eur. J. Med. Chem. 2018, 61, 2707-2724. 35. Inamura, S.; Fukase, K.; Kusumoto, S. Synthetic study of peptidoglycan partial structures. Synthesis of tetrasaccharide and octasaccharide fragments. Tetrahedron Lett. 2001, 42, 7613-7616. 36. Fujimoto, Y.; Konishi, Y.; Kubo, O.; Hasegawa, M.; Inohara, N.; Fukase, K. Synthesis of crosslinked peptidoglycan fragments for investigation of their immunobiological functions. Tetrahedron Lett. 2009, 50, 3631-3634. 37. Wang, N.; Huang, C.-y.; Hasegawa, M.; Inohara, N.; Fujimoto, Y.; Fukase, K. Glycan Sequence-Dependent Nod2 Activation Investigated by Using a Chemically Synthesized Bacterial Peptidoglycan Fragment Library. ChemBioChem 2013, 14, 482-488. 38. Chen, K.-T.; Huang, D.-Y.; Chiu, C.-H.; Lin, W.-W.; Liang, P.-H.; Cheng, W.-C. Synthesis of Diverse N-Substituted Muramyl Dipeptide Derivatives and Their Use in a Study of Human NOD2 Stimulation Activity. Chem. Eur. J. 2015, 21, 11984-11988. 39. Zemlyakov, A. E.; Tsikalov, V. V.; Kur'yanov, V. O.; Chirva, V. Y.; Bovin, N. V. Synthesis of N-Acetylmuramyl-L-Alanyl-D-Isoglutamine Aryl β-Glycosides. Russ. J. Bioorg. Chem. 2001, 27, 390-394. 40. Zemlyakov, A. E.; Tsikalov, V. V.; Kalyuzhin, O. V.; Kur'yanov, V. O.; Chirva, V. Y. N-Acetylmuramyl-L-Alanyl-D-Isoglutamine Glycosides: Effect of Glycoside Bond Configuration and Aglycone on Biological Activity. Russ. J. Bioorg. Chem. 2003, 29, 286-292. 41. Zemlyakov, A. E.; Tsikalova, V. N.; Tsikalov, V. V.; Chirva, V. Y.; Mulik, E. L.; Kalyuzhin, O. V. Synthesis and Protective Activity of β-Glycosides of N-Acetylmuramyl-L-Alanyl-D-Isoglutamine with Alkylalicyclic and Arylaliphatic Aglycons. Russ. J. Bioorg. Chem. 2005, 31, 576-582. 42. Zemlyakov, A. E.; Tsikalova, V. N.; Tsikalov, V. V.; Chirva, V. Y.; Mulik, E. L.; Kuzovlev, F. N.; Kalyuzhin, O. V.; Kiselevsky, M. V. Dialkylmethyl β-glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine: Synthesis and protective antiinfection and cytotoxic activities. Russ. J. Bioorg. Chem. 2008, 34, 103-109. 43. Zemlyakov, A. E.; Tsikalova, V. N.; Azizova, L. R.; Chirva, V. Y.; Mulik, E. L.; Shkalev, M. V.; Kalyuzhin, O. V.; Kiselevsky, M. V. Synthesis and biological activity of aryl S-β-glycosides of 1-thio-N-acetylmuramyl-L-alanyl-D-isoglutamine. Russ. J. Bioorg. Chem. 2008, 34, 223-229. 44. Zemplén Deacetylation. In Comprehensive Organic Name Reactions and Reagents. 45. Kusumoto, S.; Inage, M.; Shiba, T.; Azuma, I.; Yamamura, Y. Synthesis of long chain fatty acid esters of N-acetylmuramyl-L-alanyl-D-isoglutamine in relation to antitumor activity. Tetrahedron Lett. 1978, 19, 4899-4902. 46. Kusumoto, S.; Okada, S.; Yamamoto, K.; Shiba, T. Synthesis of 6-O-Acyl Derivatives of Immunoadjuvant Active N-Acetylmuramyl-L-alanyl-D-isoglutamine. Bull. Chem. Soc. Jpn. 1978, 51, 2122-2126. 47. Pabst, M. J.; Cummings, N. P.; Shiba, T.; Kusumoto, S.; Kotani, S. Lipophilic derivative of muramyl dipeptide is more active than muramyl dipeptide in priming macrophages to release superoxide anion. Infect. Immun. 1980, 29, 617-622. 48. Imoto, M.; Kageyama, S.; Kusumoto, S.; Kohno, M.; Matsumoto, K.; Hashimoto, S.; Tohgo, A.; Shiba, T. Synthesis and Antitumor Activity of N-Acetylmuramyl-L-alanyl-D-isoglutamine 6-Phosphate and Its Lipophilic Derivatives. Bull. Chem. Soc. Jpn. 1986, 59, 3207-3212. 49. Sharma, M.; Potti, G. G.; Simmons, O. D.; Korytnyk, W. Fluorinated carbohydrates as potential plasma membrane modifiers and inhibitors. Synthesis of 2-acetamido-2,6-dideoxy-6-fluoro-d-galactose. Carbohydr. Res. 1987, 162, 41-51. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78874 | - |
| dc.description.abstract | 細菌細胞壁的主要成分為肽聚糖， 其中肽聚糖則是由重複性的N-乙酰-葡萄糖胺以及N-乙酰-胞壁酰基酸所構成。肽聚糖中的胞壁酰基二肽 (MDP) 被發現是核苷酸結合及寡聚化結構域樣受體2 (NOD2) 的最小促進單位。MDP被發現能夠結合到NOD2上促使NOD2活化進而釋放NF-B最終導致免疫反應的發生。目前為止，科學家針對MDP的衍生物做了不少的衍生以及探討，但是其中一些分子對於NOD2的研究並沒有述說的很詳細，因此本篇論文將透過針對這些位向 (糖端，胜肽端和C4端) 進行修飾並討論這些MDP的衍生物對於NOD2活性的影響。
首先，我們啟發自之前文獻的報導，利用三胜肽 [NH2-Gly-Ala-Glu(diOEt)] 與不同的雜環進行結合以取代MDP上的糖端。在這一部分，我們總共合成了19個分子。透過NOD2活化試驗的結果，我們發現化合物55G (萘官能基取代) 有不錯的NOD2觸發活性。有趣的是化合物55F (喹啉官能基取代) 雖然結構與55G非常相似，但是活性卻比55G弱了很多。 在第二部分，我們利用實驗室之前的方法來合成勝肽修飾的衍生物。透過這個方法，我們得到了11個MDP的衍生物。細胞試驗顯示MDP上的異谷氨酸在NOD2的活化上扮演著非常重要的角色。在這些分子中化合物64D（異谷氨酸上的羧基酰亜酸取代成乙酯）被發現為其中最有活性的分子（在10 nM, 2倍於MDP的活性）。 最後， 我們針對MDP的C4部分進行修飾，利用click reaction來產生C4三唑 (triazole) 取代的衍生物。透過這個方法，我們得到了5個分子。另一方面，我們也將C1的羥基修飾成C1-卞酯 (OBn) 從而探討C1-OBn以及C4位向的影響。透過試驗，我們發現C1-OBn以及C4-三唑取代都會造成NOD2的活性下降。 透過我的努力，一共有37個最終分子被合成出來。透過這些分子我們能夠更加的了解NOD2以及MDP之間的關係。對於提高異谷氨酸上的羧基酰亞胺部位的親脂性能夠很好的提高NOD2的活性，但目前並沒有找到最好的官能基，因此針對這部分的修飾將會在未來繼續進行。 | zh_TW |
| dc.description.abstract | Peptidoglycans (PGNs) are the major components of bacterial cell walls. They comprise of a repeating disaccharide unit commonly known as N-acetyl glucosamine-N-acetyl-muramic acid. Muramyl dipeptide (MDP) is the minimal structure of bacteria’s peptidoglycan for the NOD2 activation. MDP has been demonstrated to directly bind to NOD2, which stimulated NF-B production, and triggered innate immune responses. So far, strategies for MDP analogues are mainly for its adjuvanticity, NOD2 activity or anti-infectious activity. However, there are still some potions of MDP hadn’t been fully studied, for example the contribution of functional groups extending from C4 position. Therefore, the study of saccharide, peptide and C4-position of MDP are addressed in this thesis.
Firstly, inspired from previous literature report, we applied the tripeptides [NH2-Gly-Ala-Glu(diOEt)] to couple with different heterocyclic, instead of sugar. Total 19 compounds were generated. From the NOD2 activation assay result, compound 55G, substituted by a naphthalene moiety, was found to be a potent NOD2 stimulator. Interestingly, compound 55F substituted by a quinoline moiety showed weak activity of NOD2 activation. Secondly, we modified on the peptide moiety of MDP using previous synthesis strategy developed by us. Total 11 MDP analogues were synthesized. The NOD2 assay showed that isoglutamine moiety was essential to NOD2 activation. Compound 64D, an amine moiety on isoglutamine replaced by ethoxyl moiety, was determined to be the most potent NOD2 stimulator so far (2-fold compared with MDP, 10 nM). Finally, we substituted the C4-position of MDP by triazole derivatives, sequentially coupled with azido-containing 50 yielded 5 compounds. At the same time, we also replaced the C1-OH into C1-OBn to study the C1 and C4 effect. From the NOD2 activation assay, we found both C1-OBn and C4-triazole substitution decreased the NOD2 activity. Through our effort, total 37 numbers of final compounds were generated. Based on the result, we can now have better understandings of the relationship between NOD2 and MDP more clearly. We found that modification on the peptide moiety can improve NOD2 activity. Future study on this position is needed. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:25:49Z (GMT). No. of bitstreams: 1 ntu-107-R04423025-1.pdf: 7801562 bytes, checksum: 1b3033331e09844568e31dccff939a11 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 謝誌 I
中文摘要 II Index of Figures VIII Abbreviations XI Introduction 1 1.1 Introduction of host immune response induced by bacterial cell walls 1 1.2 Pathway of NOD2 activation 2 1.3 Clinically approved MDP analogues 4 1.4 Previously studies of SAR between MDP analogues and NOD2 5 1.4.1 C2-position effect 5 1.4.2 Peptide effect on NOD2 6 1.4.3 Desmuramyldipeptide 6 1.4.4 C4-position effect 7 1.4.5 C1-position and C2-position effect 8 1.5 General synthesis method toward MDP analogues 9 1.5.1 The synthesis of C1-position substituted MDP 9 1.5.2 The synthesis of C6-position substituted MDP 10 1.6 Motivation and Design 11 Results and Discussion 16 2.1 Desmuramyldipeptide 16 2.1.1 Synthesis of desmuramyldipeptide analogues 16 2.1.2 NOD2 assay toward desmuramyldipeptide libary 17 2.1.3 Brief summary 20 2.2 Isoglutamine modified MDP 21 2.2.1 Preparation of compound 45 21 2.2.2 Synthesis of isoglutamine replaced MDP 22 2.2.3 NOD2 assay of isoglutamine replaced MDP and its analogues 24 2.2.4 Preparation of dipeptide 63A to 63E 25 2.2.5 Preparation of isoglutamine functional groups modified MDPs 26 2.2.6 NOD2 Assay for isoglutamine modified MDPs 28 2.2.7 Brief summary 30 2.3 C4-position substituted MDP analogues 31 2.3.1 Study of C4-substituted MDP analogues 31 2.3.2 Preparation of azido 50 32 2.3.3 Synthesis of C4-triazole substituted MDPs 34 2.3.4 Synthesis of C1-OBn, C4-substitued MDPs 37 2.3.5 NOD2 assay toward C4-position diversified MDPs 38 2.3.6 Brief summary 39 Summary and Prospective 41 Experimental section 43 References 93 Appendix 102 | - |
| dc.language.iso | en | - |
| dc.subject | 細菌細胞壁 | zh_TW |
| dc.subject | 細菌胞壁二? | zh_TW |
| dc.subject | 核?酸結合及寡聚化結構域樣受體 2 | zh_TW |
| dc.subject | ?聚醣 | zh_TW |
| dc.subject | immunology | en |
| dc.subject | peptides | en |
| dc.subject | innate immunity | en |
| dc.subject | peptidoglycan | en |
| dc.subject | muramyl dipeptide (MDP) | en |
| dc.subject | NOD2 | en |
| dc.title | 修飾細菌胞壁酰二肽對NOD2活性之影響 | zh_TW |
| dc.title | Modifications of bacterial cell wall Muramyl Dipeptides toward NOD2 stimulation study | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 107-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.coadvisor | 鄭偉杰 | zh_TW |
| dc.contributor.coadvisor | Wei-Chieh Cheng | en |
| dc.contributor.oralexamcommittee | 吳盈達 | zh_TW |
| dc.contributor.oralexamcommittee | Ying-Ta Wu | en |
| dc.subject.keyword | ?聚醣,細菌細胞壁,細菌胞壁二?,核?酸結合及寡聚化結構域樣受體 2, | zh_TW |
| dc.subject.keyword | NOD2,muramyl dipeptide (MDP),peptidoglycan,immunology,innate immunity,peptides, | en |
| dc.relation.page | 155 | - |
| dc.identifier.doi | 10.6342/NTU201804311 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-11-29 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | 2024-03-11 | - |
| 顯示於系所單位： | 藥學系 | |
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