Design and Synthesis of Inhibitors against SARS Coronavirus: Ⅰ alpha-Hydroxy Amide and alpha-Ketoamide Ⅱ Glycyrrhizin Derivatives
Date Issued
2006
Date
2006
Author(s)
Li, Yu-Ting
DOI
zh-TW
Abstract
The aim of this thesis is to discover the antiviral agents against severe acute respiratory syndrome coronavirus (SARS-CoV). This thesis consists of two parts: (i) synthesis of alpha-hydroxy amide and alpha-keto amide derivatives, and (ii) synthesis of glycyrrhetinic acid derivatives.
The derivatives of alpha-hydroxy amide and alpha-keto amide, such as 12 and 13 were synthesized, in order to mimic the tetrahedral transition state in the hydrolysis of the peptide substrate catalyzed by the SARS-CoV main protease. The inhibition assays were carried out using a peptide substrate that contains a fluorophore Edans and a quencher Dabcyl.
It has been reported that Glycyrrhizin has the activity to inhibit the replication of the SARS coronavirus, but the inhibition concentration is still high. The mechanism of glycyrrhizic acid in vivo is still unclear. It is thus desirable to find better SARS-CoV inhibitors. The structure of Glycyrrhizin contains two parts: 18 beta glycyrrhetinic acid (GA) and disaccharide acid. A series of GA derivatives were prepared by coupling reactions with amino acid esters, and their anti-SARS activities were measured using the CPE (cytopathic effect) assay.
We found that a glycyrrhetinic acid derivative (JMF479) was particularly effective against the SARS coronavirus with the IC50 and CPE values of 17 and 3.3 mucroM.
Subjects
嚴重急性呼吸道症候群
羥基醯胺
酮基醯胺
甘草素
SARS
hydroxyamide
ketoamide
glycyrrhizin
Type
thesis
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