Aglycone-focused randomization of 2-difluoromethylphenyl-type sialoside suicide substrates for neuraminidases

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• 作者：Hirokazu Kai ; Hiroshi Hinou ; ^{hinou@sci.hokudai.ac.jp} ; Shin-Ichiro Nishimura
• 关键词：Neuraminidase ; Suicide substrate ; Mechanism-based inhibitor ; Focused library ; Aglycone
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 April, 2012
• 卷：20
• 期：8
• 页码：2739-2746
• 文件大小：840 K

摘要

A selective and potent inhibitor of neuraminidases, a hydrolase that is responsible for processing sialylated glycoconjugates, is a promising drug candidate for various infective diseases. The current study demonstrates that the use of an aglycone-focused library of 2-difluoromethylphenyl 伪-sialosides is an effective technique to find potent and selective mechanism-based labeling reagents for neuraminidases. The focused library was constructed from a 4-azide-2-difluoromethylphenyl sialoside (2) and an alkyne-terminated compound library by a click reaction. The focused library showed different inhibition patterns for two neuraminidases, Vibrio cholerae neuraminidase (VCNA) and human neuraminidase 2 (hNeu2), and the most potent inhibitors for each neuraminidase were selected. A kinetic analysis of the selected inhibitors demonstrated that the modification of the aglycone moiety improved the K_I value with little change in the t_1/2 value of the enzyme activity relative to the basic skeleton (2).