研究生: |
劉宛瑄 LIU, WAN-HSUAN |
---|---|
論文名稱: |
結核病藥物開發:設計合成麥芽糖轉移酶抑制劑 Drug Discovery for Anti-Tuberculosis: Design and Synthesis of Maltosetransferase Inhibitors |
指導教授: |
謝俊結
Shie, Jiun-Jie 林文偉 Lin, Wen-Wei |
學位類別: |
碩士 Master |
系所名稱: |
化學系 Department of Chemistry |
論文出版年: | 2019 |
畢業學年度: | 107 |
語文別: | 中文 |
論文頁數: | 111 |
中文關鍵詞: | 麥芽糖轉移酶 、麥芽糖轉移酶抑制劑 、高通量篩選 、細菌影像測試 、CuAAC 、sulfonamido-oxine-based fluorescent |
英文關鍵詞: | maltose transferase, maltose transferase inhibitor, high throughput screening, bacterial imaging test, CuAAC, sulfonamido-oxine-based fluorescent |
DOI URL: | http://doi.org/10.6345/NTNU201900977 |
論文種類: | 學術論文 |
相關次數: | 點閱:128 下載:0 |
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結核病(Tuberculosis ,簡稱TB)是一種全球普遍性流行疾病,全球多重抗藥性結核桿菌(MDR)TB的例子日益嚴重增加,這說明需要開發一種治療結核病的新藥。參與細菌細胞壁合成α-D-葡聚醣 (α-D-glucan)成份的結核分枝桿菌麥芽糖轉移酶(Mtb GlgE)是近年來發現為結核桿菌生長的特定必需酶,適合用於設計抑制結核菌生長的目標酵素。在本論文中,我們合理設計了一系列模擬過渡態的類似物作為GlgE酶抑制劑,透過用氮原子取代醣苷 (glycosides) 的內環氧原子,將iminosugars和pseudo-醣苷上含有氮雜環官能基,作為與另一種醣苷相連的結構支架,希望藉由酶活性中心與分子所產生的電荷作用力用於抑制GlgE酶。此外,我們設計了螢光基質用於檢測GlgE酶活性指標,以磺酰氨基氧化物為螢光基團的sulfonamido-oxine-based fluorescent maltose-1-phosphates (Sox-M1P)作為主體基質,當發光團結合Mg2+,並在GlgE水解Sox-M1P後,藉由螯合增強螢光(CHEF)反應機制,以螢光強度變化達到高靈敏快速檢測的效果。另一方面,在本論文中,我們也描述了利用炔基修飾的單醣衍生物(GlcNAl,ManNAl,GalNAl和Fucyne)作為探針,藉由醣代謝生成途徑標記細菌壁中的醣共軛體 (glycoconjugates)策略。搭配一價銅離子催化疊氮-炔正交性化學反應偶合炔基官能化螢光探針的策略,希望以螢光顯影的方式檢測和區分不同菌株細胞壁表面醣共軛體,達到肉眼快速檢測的目的。
Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug-resistant (MDR) TB worldwide underlines the need to develop a new drug to treat the infectious disease. Mycobacterium tuberculosis maltosyltransferase (Mtb GlgE) involved in α-D-glucan is an essential enzyme only for tuberculosis growth. We designed a series of transition-state mimic analogues as inhibitors against GlgE by replacing the endocyclic oxygen atom of glycosides with a nitrogen atom, the iminosugars and fusing membered nitrogen heterocyclic ring into the pseudo-glycoside as the structural scaffold that is linked to another glycoside for inhibiting GlgE. In addition, we designed a fluorescence dye, sulfonamido-oxine-based fluorescent maltose-1-phosphates (Sox-M1P), the chromophore binds Mg2+ and undergoes chelation-enhanced fluorescence (CHEF) upon hydrolysis of Sox-M1P by GlgE. On the other hand, we describe a metabolic oligosaccharide engineering (MOE) strategy for exploiting sugar metabolic pathways to label glycocojugates in bacteria with alkyne-modified sugar substrates (GlcNAl, ManNAl, GalNAl and Fucyne). Subsequent CuAAC [Cu(I) catalyzed Azide-Alkyne Cycloaddition] reaction with azide-functionalized probes enabled fluorescent detection and visualization of bacteria.
[1] Tra, V. N.; Dube, D. H. Chem. Commun. 2014, 50, 4659–4673. Glycans in Pathogenic Bacteria – Potential for Targeted Covalent Therapeutics and Imaging Agents.
[2] Sadamoto, R.; Niikura, K.; Sears, P. S.; Liu, H.; Wong, C. H.; Suksomcheep, A.; Tomita, F.; Monde, K.; Nishimura, S. I. J. Am. Chem. Soc. 2002, 124, 9018–9019. Cell-Wall Engineering of Living Bacteria.
[3] Kuru, E.; Hughes, H. V.; Brown, P. J.; Hall, E.; Tekkam, S.; Cava, F.; De Pedro, M. A.; Brun, Y. V.; VanNieuwenhze, M. S. Angew. Chem. Int. Ed. 2012, 51, 12519–12523. In Situ Probing of Newly Synthesized Peptidoglycan in Live Bacteriawith Fluorescent D-Amino Acids.
[4] Siegrist, M. S.; Whiteside, S.; Jewett, J. C.; Aditham, A.; Cava, F.; Bertozzi, C. R. ACS Chem. Biol. 2013, 8, 500–505. D Amino Acid Chemical Reporters Reveal Peptidoglycan Dynamics of an Intracellular Pathogen.
[5] Dumont, A.; Malleron, A.; Awwad, M.; Dukan, S.; Vauzeilles, B. Angew. Chem. Int. Ed. 2012, 51, 3143–3146. Click-Mediated Labeling of Bacterial Membranes through Metabolic Modification of the Lipopolysaccharide Inner Core.
[6] Swarts, B. M.; Holsclaw, C. M.; Jewett, J. C.; Alber, M.; Fox, D. M.; Siegrist, M. S.; Leary, J. A.; Kalscheuer, R.; Bertozzi, C. R. J. Am. Chem. Soc. 2012, 134, 16123–16126. Probing the Mycobacterial Trehalome with Bioorthogonal Chemistry.
[7] Liu, F.; Aubry, A. J.; Schoenhofen, I. C.; Logan, S. M.; Tanner, M. E. ChemBioChem 2009, 10, 1317–1320. The Engineering of Bacteria Bearing Azido‐Pseudaminic Acid‐Modified Flagella.
[8] Champasa, K.; Longwell, S. A.; Eldridge, A. M.; Stemmler, E. A.; Dube, D. H. Mol. Cell Proteomics 2013, 12, 2568–2586. Targeted Identification of Glycosylated Proteins in the Gastric Pathogen Helicobacter Pylori (Hp).
[9] Kaewsapsak, P.; Esonu, O.; Dube, D. H. ChemBioChem 2013, 14, 721–726. Recruiting the Host's Immune System to Target Helicobacter Pylori's Surface Glycans.
[10] Memmel, E.; Homann, A.; Oelschlaeger, T. A.; Seibel, J. Chem. Commun. 2013, 49, 7301–7303. Metabolic Glycoengineering of Staphylococcus Aureus Reduces Its Adherence to Human T24 Bladder Carcinoma Cells.
[11] Shieh, P.; Bertozzi, C. R. Org. Biomol. Chem. 2014, 12, 9307–9320. Design Strategies for Bioorthogonal Smart Probes.
[12] Shih, H. W.; Kamber, D. N.; Prescher, J. A. Curr. Opin. Chem. Biol. 2014, 21, 103–111. Building Better Biorthogonal Reactions.
[13] World Health Organization. The Global Tuberculosis Report 2013, World Health Organization, France, 2013.
[14] Taiwan Centers for Disease Control.
[15] Zumla, A.; Raviglione, M.; Hafner, R.; von Reyn, C. F. N. Engl. J. Med. 2013, 368, 745–755. Tuberculosis.
[16] Zhang, Y. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 529–564. The Magic Bullets and Tuberculosis Drug Targets.
[17] Chetty, S.; Ramesh, M.; Singh-Pillay, A.; Soliman, M. E.S. Bioorg. Med. Chem. Lett. 2017, 27, 370–386. Recent Advancements in the Development of Anti-Tuberculosis Drugs.
[18] Daniel, T. M. N. Engl. J. Med. 1969, 280, 615–616. Rifampin – A Major New Chemotherapeutic Agent for the Treatment of Tuberculosis.
[19] World Health Organization, 20th ed. World Health Organization. 2015, 1–115. Global Tuberculosis Report.
[20] Velayati, A. A.; Masjedi, M. R.; Farnia, P.; Tabarsi, P.; Ghanavi, J.; ZiaZarifi, A. H.; Hoffner, S. E. Chest. 2009, 136, 420–425. Emergence of New Forms of Totally Drug–Resistant Tuberculosis Bacilli: Super Extensively Drug-Resistant Tuberculosis or Totally Drug-Resistant Strains in Iran.
[21] Udwadia, Z. F.; Amale, R. A.; Ajbani, K. K.; Rodrigues, C. Clin. Infect. Dis. 2012, 54, 579–581. Totally Drug-Resistant Tuberculosis in India.
[22] Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report (MMWR), 2013, 62, 1-12. Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis.
[23] Kalscheuer, R.; Syson, K.; Veeraraghavan, U.; Weinrick, B.; Biermann, K. E.; Liu, Z.; Sacchettini, J. C.; Besra, G.;, Bornemann, S.; Jacobs Jr, W. R. Nat. Chem. Biol. 2010, 6, 376–384. Self-Poisoning of Mycobacterium Tuberculosis by Targeting GlgE in an α-Glucan Pathway.
[24] Kalscheuer, R.; Koliwer-Brandl, H. Microbiol Spectrum 2014, 2, no. 3. Genetics of Mycobacterial Trehalose Metabolism.
[25] Syson, K.; Stevenson, C. E. M.; Rashid, A. M.; Saalbach, G.; Tang, M.; Tuukkanen, A.; Svergun, D. I.; Withers, S. G.; Lawson, D. M.; Bornemann, S. Biochemistry 2014, 53, 2494−2504. Structural Insight into How Streptomyces Coelicolor Maltosyl Transferase GlgE Binds α‑Maltose 1‑Phosphate and Forms a Maltosyl-Enzyme Intermediate.
[26] Lindenberger, J. J.; Veleti, S. K.; Wilson, B. N.; Sucheck, S. J.; Ronning, D. R. Sci. Rep. 2015, 5, 12830–12841. Crystal Structures of Mycobacterium Tuberculosis GlgE and Complexes with Non-Covalent Inhibitors.
[27] Veleti, S. K.; Lindenberger, J. J.; Ronning, D. R.; Sucheck, S. J. Bioorg. Med. Chem. 2014, 22, 1404–1411. Synthesis of a C-Phosphonate Mimic of Maltose-1-Phosphateand Inhibition Studies on Mycobacterium Tuberculosis GlgE.
[28] Veleti, S. K.; Lindenberger, J. J.; Thanna, S.; Ronning, D. R.; Sucheck, S. J. J. Org. Chem. 2014, 79, 9444−9450. Synthesis of a Poly-hydroxypyrolidine-Based Inhibitor of
Mycobacterium Tuberculosis GlgE.
[29] Borsari, C.; Ferrari, S.; Venturelli, A.; Costi, M. P. Drug Discovery Today 2017, 22, 576–584. Target-Based Approaches for the Discovery of New Anti Mycobacterial Drugs.
[30] Thanna, S.; Lindenberger, J. J,; Gaitonde, V. V.; Ronning, D. R.; Sucheck, S. J. Org. Biomol. Chem. 2015, 13, 7542–7550. Synthesis of 2-Deoxy-2,2-Difluoro-α-Maltosyl Fluoride and Its X-ray Structure in Complex with Streptomyces Coelicolor GlgEI-V279S.
[31] Shie, J. J.; Liu, Y. C.; Lee, Y. M.; Lim, C.; Fang, J. M.; Wong, C. H. J. Am. Chem. 2014, 136, 9953−9961. An Azido-BODIPY Probe for Glycosylation: Initiation of Strong
Fluorescence upon Triazole Formation.
[32] Vonhoff, S.; Piens, K.; Pipelier, M.; Braet, C.; Claeyssens, M.; Vasella, A. Helvetica Chimica Acta 1999, 82, 963–980. Inhibition of Cellobiohydrolases from Trichoderma reesei. Synthesis and Evaluation of Some Glucose-, Cellobiose-,and Cellotriose-Derived Hydroximolactams and Imidazoles.
[33] Warthaka, M.; Adelmann, C. H.; Kaoud, T. S.; Edupuganti, R.; Yan, C.; Johnson Jr., W. H.; Ferguson, S.; Tavares, C. D.; Pence, L. J.; Anslyn, E. V.; Ren, P.; Tsai, K. Y.; Dalby, K. N. ACS Med. Chem. Lett. 2015, 6, 47−52. Quantification of a Pharmacodynamic ERK End Point in Melanoma Cell Lysates: Toward Personalized Precision Medicine.
[34] Shults, M. D.; Pearce, D. A.; Imperiali, B. J. AM. CHEM. SOC. 2003, 125, 10591-10597. Modular and Tunable Chemosensor Scaffold for Divalent Zinc.
[35] Vonhoff, S.; Vasella, A. Synth. Commun. 1999, 29, 551–560.
[36] Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512–7515. NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities.
[37] Motawia, M. S.; Olsen, C. E.; Møller, B. L.; Marcussen, J. Carbohydrate Research 1994, 252, 69-84. Chemical Synthesis and NMR Spectra of a Protected Branched-Tetrasaccharide Thioglycoside, a Useful Intermediate for the Synthesis of Branched Oligosaccharides