Design, Synthesis, Biological Activity, and Complexed Structure of SARS-CoV 3CL Protease Inhibitors: (i) Trifluoromethyl Ketones and (ii) C2-Symmetric Diols
Date Issued
2006
Date
2006
Author(s)
Shao, Yi-Ming
DOI
en-US
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.
Subjects
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
SDGs
Type
other
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