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

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.