Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors - Carbohydrate Chemistry: Chemical and Biological Approaches - page 418

Conformationally restricted glycoside
derivatives as mechanistic probes and/or
inhibitors of sugar processing enzymes
and receptors
Carine Maaliki, a Charles Gauthier, b Olivier Massinon, a
Ram Sagar, b St ´ phane P. Vincent* a and Yves Bl ´ riot* b
DOI: 10.1039/9781849739986-00418
X-ray crystallography and kinetic isotopic effects applied to glycosyl-processing enzymes
in complex with their substrates or inhibitors allowed deciphering of the sugar ring
conformation at the atomic level. This information, crucial for the development of potent
and selective inhibitors of these enzymes, has been extensively exploited to design
conformationally restricted sugar analogues. This chapter gives an overview of the main
classes of conformationally restricted sugar analogues aimed at interfering with hydrolytic
and non-hydrolytic glycosyl-processing enzymes that have been reported in the literature.
1 Introduction
The knowledge of enzyme mechanism is not only fundamental to
understand the basic principles of biocatalysis, but it can also lead to the
design and the synthesis of potent inhibitors of biologically relevant
enzymes. The development of the mechanism-based glycosidase
inhibitor Relenza and its validation as a drug to treat influenza virus
infections is probably one of the most significant achievement of this
research field, 1 still inspiring new prototypes. 2 Together with the crystal
structure analysis of glycosyl-processing enzymes/inhibitor/substrate
complexes and the measurements of kinetic isotopic effects (KIE) of
isotopically labelled sugars and analogues, the biological evaluation and
spectroscopic analysis of synthetic inhibitors rationally designed also
strongly contribute to the elucidation of the mechanism of action of
many glycoside processing enzymes at the atomic level. The hydroxyl
pattern and the presence of a positive or negative charge are usually
compulsory to achieve good mimicry to the glycosyl-processing enzymes
transition state (TS). Thanks to the tools depicted above (X-ray crystal-
lography, KIE) allowing access to the conformational information
associated with the sugar ring, the impact of the sugar ring conform-
ation 3 on inhibition and binding is now well recognized.
The aim of this review is to give an overview of the main classes of
synthetic glycoside analogues restrained in a defined conformation that
have been elaborated to produce potent and selective inhibitors of a