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

Kai, Hirokazu  ,  Hinou, Hiroshi  ,  Nishimura, Shin-Ichiro

Bioorganic & Medicinal Chemistry
20 ( 8 )  , pp.2739 - 2746 , 2012-04-15 , Elsevier
ISSN:0968-0896
Description
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 α-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 KI value with little change in the t_[1/2] value of the enzyme activity relative to the basic skeleton (2).

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