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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 Design, Synthesis, Biological Activity, and Complexed Structure of SARS-CoV 3CL Protease Inhibitors: (i) Trifluoromethyl Ketones and (ii) C2-Symmetric Diols |
Authors: | Yi-Ming Shao 邵奕鳴 |
Advisor: | 翁啟惠(Chi-Huey Wong) |
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, protease inhibitors,trifluoromethyl ketones,C2-symmetric diols,computer modeling,X-ray crystallography, |
Publication Year : | 2006 |
Degree: | 碩士 |
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. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34401 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 生化科學研究所 |
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ntu-95-1.pdf Restricted Access | 17.45 MB | Adobe PDF |
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