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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 翁啟惠(Chi-Huey Wong) | |
| dc.contributor.author | Yi-Ming Shao | en |
| dc.contributor.author | 邵奕鳴 | zh_TW |
| dc.date.accessioned | 2021-06-13T06:06:45Z | - |
| dc.date.available | 2008-06-22 | |
| dc.date.copyright | 2006-06-22 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-06-11 | |
| dc.identifier.citation | Chapter One
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A 3D model of SARS-CoV 3CL proteinase and its inhibitors design by virtual screening. Acta. Pharmacol. Sin. 24, 497–504 (2003). 17. Yang, H. et al. The crystal structure of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc. Natl. Acad. Sci. USA 100, 13190–13195 (2003). 18. Anand, K., Ziebuhr J., Wadhwani, P., Mesters, J.R. & Hilgenfeld, R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300, 1763–1767 (2003). 19. Bacha, U., Barrila, J., Velazquez-Campoy, A., Leavitt, S.A., & Freire, E. Identification of novel inhibitors of the SARS coronavirus main protease 3CLpro. Biochemistry 43, 4906–4912 (2004). 20. Kao, R.Y. et al. Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics. Chem. Biol. 11, 1293–1299 (2004). 21. Blanchard, J.E. et al. High-throughput screening identifies inhibitors of the SARS coronavirus main proteinase. 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Stable benzotriazole esters as mechanism-based inactivators of the severe acute respiratory syndrome 3CL protease. Chem. Biol. 13, 261–268 (2006). 28. Ghosh, A.K. et al. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors. J. Med. Chem. 48, 6767–6771 (2005). 29. Yang, H. et al. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol. 3, e324 (2005). 30. Lee, T.-W. et al. Crystal Structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like aza-peptide epoxide. J. Mol. Biol. 353, 1137–1151 (2005). 31. Wu, C.-Y. et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc. Natl. Acad. Sci. USA 101, 10012–10017 (2004). Chapter Two 1. Gelb, M.H., Svaren, J.P. & Abeles, R.H. Fluoro ketone inhibitors of hydrolytic enzymes. Biochemistry 24, 1813–1817 (1985). 2. (a) Edwards, P.D. et al. Discovery and biological activity of orally active peptidyl trifluoromethyl ketone inhibitors of human neutrophil elastase. J. Med. Chem. 40, 1876–1885 (1997). (b) Veale, C.A. et al. Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase. J. Med. Chem. 40, 3173–3181 (1997). 3. Leung, D., Abbenante, G. & Fairlie, D.P. Protease inhibitors: current status and future prospects. J. Med. Chem. 43, 305–341 (2000). 4. Human neutrophil elastase: Edwards, P.D. & Bernstein, P.R. Synthetic inhibitors of elastase. Med. Res. Rev. 14, 127–194 (1994). 5. (a) Edwards, P.D. et al. Design, synthesis, and kinetic evaluation of a unique class of elastase inhibitors, the peptidyl α-ketobenzoxazoles, and the x-ray crystal structure of the covalent complex between porcine pancreatic elastase and Ac-Ala-Pro-Val-2-benzoxazole. J. Am. Chem. Soc. 114, 1854–1863 (1992). (b) Stein, R.L. et al. Mechanism of slow-binding inhibition of human leukocyte elastase by trifluoromethyl ketones. Biochemistry 26, 2682–2689 (1987). (c) Govardhan, C.P. & Abeles, R.H. Structure-activity studies of fluoroketone inhibitors of alpha-lytic protease and human leukocyte elastase. Arch. Biochem. Biophys. 280, 137–146 (1990). (d) Peet, N.P. et al. Synthesis of peptidyl fluoromethyl ketones and peptidyl alpha-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G. J. Med. Chem. 33, 394–407 (1990). 6. Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action, 2nd edn., Ch. 5 (Academic Press, San Diego, 2004). 7. Takahashi, L.H., Radhakrishnan, R., Resenfield, R.E., Meyer, E.F. & Trainor, D.A. Crystal structure of the covalent complex formed by a peptidyl α,α-difluoro-β-keto amide with porcine pancreatic elastase at 1.78-Å resolution. J. Am. Chem. Soc. 111, 3368–3374 (1989). 8. Pesenti, C. & Viani, F. The influence of fluorinated molecules (semiochemicals and enzyme substrate analogues) on the insect communication system. ChemBioChem 5, 590–613 (2004). 9. (a) α-Chymotrypsin: Imperiali, B & Abeles, R.H. Inhibition of serine proteases by peptidyl fluoromethyl ketones. Biochemistry 25, 3760–3767 (1986). (b) Human cytomegalovirus protease: LaPlante, S.R. et al. Characterization of the human cytomegalovirus protease as an induced-fit serine protease and the implications to the design of mechanism-based inhibitors. J. Am. Chem. Soc. 121, 2974–2986 (1999). Ogilvie, W. et al. Peptidomimetic inhibitors of the human cytomegalovirus protease. J. Med. Chem. 40, 4113–4135 (1997). 10. (a) Cathepsin G: Peet, N.P. et al. Synthesis of peptidyl fluoromethyl ketones and peptidyl α-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G. J. Med. Chem. 33, 394–407 (1990). (b) Cathepsin B: Smith, R.A., Copp, L.J., Donnelly, S.L., Spencer, R.W. & Krantz, A. Inhibition of cathepsin B by peptidyl aldehydes and ketones: slow-binding behavior of a trifluoromethyl ketone. Biochemistry 27, 6568–6573 (1988). 11. Imperiali, B. & Abeles, R.H. A versatile synthesis of peptidyl fluoromethyl ketones. Tetrahedron Lett. 27, 135–138 (1986). 12. Poupart, M.-A., Fazal, G., Goulet, S. & Mar L.T. Solid-phase synthesis of peptidyl trifluoromethyl ketones. J. Org. Chem. 64, 1356–1361 (1999). 13. Kolb, M., Barth, J. & Neises, B. Synthesis of fluorinated α-amino ketones. Part I: α-benzamidoalkyl mono- di- and trifluoromethyl ketones. Tetrahedron Lett. 27, 1579–1582 (1986). 14. Derstine, C.W., Smith, D.N. & Katzenellenbogen, J.A. Trifluoromethyl-substituted imidazolines: novel precursors of trifluoromethyl ketones amenable to peptide synthesis. J. Am. Chem. Soc. 118, 8485–8486 (1996). 15. Boivin, J., Kaim, L.E. & Zard, S.Z. A new and efficient synthesis of trifluoromethyl ketones from carboxylic acids. Part I. Tetrahedron 51, 2573–2584 (1995). 16. Patel, D.V., Rielly-Gauvin, K. & Ryono, D.E. Peptidic trifluoromethyl alcohols and ketones. A general synthesis and application as renin inhibitors. Tetrahedron Lett. 29, 4665–4668 (1988). 17. Mancuso, A.J. & Swern D. Activated dimethyl sulfoxide: useful reagents for synthesis. Synthesis 165–185 (1981). 18. Kwon, D.S. et al. Dissection of glutathionylspermidine synthetase/amidase from Escherichia coli into autonomously folding and functional synthetase and amidase domains. J. Biol. Chem. 272, 2429–2436 (1997). 19. Gogoi, P., Sarmah, G.K. & Konwar, D. DMSO/N2H4•H2O/I2/H2O/CH3CN: A new system for selective oxidation of alcohols in hydrated media. J. Org. Chem. 69, 5153–5154 (2004). 20. Kuo, C.-J., Chi, Y.-H., Hsu, T.-A. & Liang, P.-H. Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate. Biochem. Biophys. Res. Commun. 318, 862–867 (2004). 21. Brady, K. & Abeles, R.H. Inhibition of chymotrypsin by peptidyl trifluoromethyl ketones: determinants of slow-binding kinetics. Biochemistry 29, 7608–7617 (1990). 22. Iijima, K., Katada, J., Yasuda, E., Uno, I. & Hayashi, Y. N-[2,2-Dimethyl-3-(N-(4-cyanobenzoyl)amino)nonanoyl]-L-phenylalanine ethyl ester as a stable ester-type inhibitor of chymotrypsin-like serine proteases: structural requirements for potent inhibition of α-chymotrypsin. J. Med. Chem. 42, 312–323 (1999). Chapter Three 1. Ogden, R.C. & Flexner, C.W. Protease Inhibitors in AIDS Therapy Ch. 1 (Marcel Dekker, New York, 2001). 2. Ghosh, A.K., Bilcer, G. & Schiltz, G. Syntheses of FDA approved HIV protease inhibitors. Synthesis 2203–2229 (2001). 3. (a) Navia, M.A. et al. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 337, 615–620 (1989). (b) Wlodawer, A. et al. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245, 616–621 (1989). 4. Brik, A. & Wong, C.-H. HIV-1 protease: mechanism and drug discovery. Org. Biomol. Chem. 1, 5–14 (2003). 5. Kempf, D.J. et al. Structure-based, C2 symmetric inhibitors of HIV protease. J. Med. Chem. 33, 2687–2689 (1990). 6. Kempf, D.J. et al. Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy. J. Med. Chem. 41, 602–617 (1998). 7. Sham, H.L. et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother. 42, 3218–3224 (1998). 8. Mo, H. et al. Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: mutation patterns and baseline correlates. J. Virol. 79, 3329–3338 (2005). 9. Lee, T. et al. Analysis of the S3 and S3′ subsite specificities of feline immunodeficiency virus (FIV) protease: development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo. Proc. Natl. Acad. Sci. USA 95, 939–944 (1998). 10. Lee, T. et al. Development of a new type of protease inhibitors, efficacious against FIV and HIV variants. J. Am. Chem. Soc. 121, 1145–1155 (1999). 11. Li, M. et al. Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease. Proteins: Struct., Funct., Genet. 38, 29–40 (2000). 12. Bühler, B. et al. Viral evolution in response to the broad-based retroviral protease inhibitor TL-3. J. Virol. 75, 9502–9508 (2001). 13. Huitron-Resendiz, S. et al. Resolution and prevention of feline immunodeficiency virus-induced neurological deficits by treatment with the protease inhibitor TL-3. J. Virol. 78, 4525–4532 (2004). 14. Rozières, S. et al. Assessment of FIV-C infection of cats as a function of treatment with the protease inhibitor, TL-3. Retrovirology 1:38 (2004). 15. Wu, C.-Y. et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc. Natl. Acad. Sci. USA 101, 10012–10017 (2004). 16. Wachtmeister, J. et al. Impact of the central hydroxyl groups on the activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid. Tetrahedron 56, 3219–3225 (2000). 17. Alterman, M. et al. Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1'-modified HIV-1 protease inhibitors. J. Med. Chem. 42, 3835–3844 (1999). 18. Mühlman, A., Classon, B., Hallberg, A. & Samuelsson, B. Synthesis of potent C2-symmetric, diol-based HIV-1 protease inhibitors. Investigation of thioalkyl and thioaryl P1/P1' substituents. J. Med. Chem. 44, 3402–3406 (2001). 19. Gurjar, M.K., Pal, S. & Rama Rao, A.V. 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Chem. 13, 5240–5252 (2005). 25. Anand, K., Ziebuhr J., Wadhwani, P., Mesters, J.R. & Hilgenfeld, R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300, 1763–1767 (2003). 26. Yang, H. et al. The crystal structure of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc. Natl. Acad. Sci. USA 100, 13190–13195 (2003). 27. Munoz, B., Giam, C.-Z. & Wong, C.-H. α-Ketoamide Phe-Pro isostere as a new core structure for the inhibition of HIV protease. Bioorg. Med. Chem. 2, 1085–1090 (1994). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34401 | - |
| dc.description.abstract | Severe acute respiratory syndrome (SARS) is a new viral infectious disease caused by a novel coronavirus (SARS-CoV). Currently, no effective antiviral agents exist against this type of virus. This thesis comprises the design, synthesis, biological activity, and complexed structures of two types of small molecules as inhibitors of SARS-CoV 3CL protease: (i) trifluoromethyl ketones and (ii) C2-symmetric diols.
Trifluoromethyl ketones are known to be reversible inhibitors of some serine proteases, such as elastase and chymotrypsin. The best one of a series of trifluoromethyl ketones synthesized is a tetrapeptidyl trifluoromethyl ketone with Ki value of 0.286 μM against SARS-CoV 3CL protease, a cysteine protease. In addition, TL-3, a potent inhibitor of HIV protease, was previously found to show inhibition (Ki = 0.6 μM) against SARS-CoV 3CL protease. Without guidance of the crystal structure of this enzyme in complex with TL-3, optimization of this inhibitor was performed based on computational modeling prediction. Aided by modeling, two novel TL-3 derivatives 163 and 168 with indole instead of benzyl group as the core were synthesized. These two new compounds were proved to be more effective inhibitors (Ki = 0.340 and 0.073 μM, respectively) than TL-3 for SARS-CoV 3CL protease. The interactions between 163 and SARS-CoV 3CL protease were determined using the combination of X-ray crystallography and computer modeling, and an molecular insight of small molecule-biological target interactions was disclosed. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T06:06:45Z (GMT). No. of bitstreams: 1 ntu-95-R92b46018-1.pdf: 17869313 bytes, checksum: a9ff72e27712f1ea679054a2bedda410 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | Chapter 1 Introduction........................................................................................ 1
1.1 Severe Acute Respiratory Syndrome (SARS)…………………………...1 1.2 SARS-CoV……………………………………………………………... 1 1.3 SARS-CoV 3CL Protease and its Inhibitors…………………………….5 1.4 References……………………………………………………………...13 Chapter 2 Trifluoromethyl Ketones...............................................................16 2.1 History of Development…………………………………………........ 16 2.2 Synthesis of Trifluoromethyl Ketones………………………………...20 2.3 Biological Activity………………………………………………….....33 2.4 Crystal Structure Analysis & Computer Modeling…………………....41 2.5 Experimental Section……………………………………………….....42 2.6 References…………………………………………………………......67 Chapter 3 C2-Symmetric Diols……………………………………………… 70 3.1 History of Development……………………………………………….70 3.2 Synthesis and Activity of C2-Symmetric Diols………………………..77 3.3 Crystal Structure Analysis & Computer Modeling…………..............106 3.4 Experimental Section………………………………………………...108 3.5 References……………………………………………………………181 3.6 Thesis Summary……………………………………………………...184 Appendix Selected Spectra…………………………………………………. 185 | |
| dc.language.iso | en | |
| dc.subject | X光結晶學 | zh_TW |
| dc.subject | 電腦模型 | zh_TW |
| dc.subject | 抑制劑 | zh_TW |
| dc.subject | 蛋白酶 | zh_TW |
| dc.subject | C2-對稱雙醇 | zh_TW |
| dc.subject | 三氟甲基酮 | zh_TW |
| dc.subject | protease inhibitors | en |
| dc.subject | computer modeling | en |
| dc.subject | C2-symmetric diols | en |
| dc.subject | trifluoromethyl ketones | en |
| dc.subject | X-ray crystallography | en |
| dc.title | 設計與合成 (1)三氟甲基酮 (2)C2-對稱雙醇 作為SARS冠狀病毒3CL蛋白酶抑制劑，以及生物活性並在結構上的研究 | zh_TW |
| dc.title | Design, Synthesis, Biological Activity, and Complexed Structure of SARS-CoV 3CL Protease Inhibitors:
(i) Trifluoromethyl Ketones and (ii) C2-Symmetric Diols | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 林俊宏(Chun-Hung Lin) | |
| dc.contributor.oralexamcommittee | 楊文彬(Wen-Bin Yang),方俊民(Jim-Min Fang) | |
| dc.subject.keyword | 蛋白酶,抑制劑,三氟甲基酮,C2-對稱雙醇,電腦模型,X光結晶學, | zh_TW |
| dc.subject.keyword | protease inhibitors,trifluoromethyl ketones,C2-symmetric diols,computer modeling,X-ray crystallography, | en |
| dc.relation.page | 308 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-06-12 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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