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Angew Chem Int Ed Engl ; 53(22): 5700-5, 2014 May 26.
Article in English | MEDLINE | ID: mdl-24737687

ABSTRACT

Oligosaccharides of the glycolipids and glycoproteins at the outer membranes of human cells carry terminal neuraminic acids, which are responsible for recognition events and adhesion of cells, bacteria, and virus particles. The synthesis of neuraminic acid containing glycosides is accomplished by intracellular sialyl transferases. Therefore, the chemical manipulation of cellular sialylation could be very important to interfere with cancer development, inflammations, and infections. The development and applications of the first nanomolar fluorescent inhibitors of sialyl transferases are described herein. The obtained carbohydrate-nucleotide mimetics were found to bind all four commercially available and tested eukaryotic and bacterial sialyl transferases in a fluorescence polarization assay. Moreover, it was observed that the anionic mimetics intruded rapidly and efficiently into cells in vesicles and translocated to cellular organelles surrounding the nucleus of CHO cells. The new compounds inhibit cellular sialylation in two cell lines and open new perspectives for investigations of cellular sialylation.


Subject(s)
Cytidine Monophosphate/analogs & derivatives , Enzyme Inhibitors/metabolism , Fluorescent Dyes/chemistry , Sialic Acids/chemistry , Sialyltransferases/metabolism , Animals , Binding Sites , CHO Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Cytidine Monophosphate/chemistry , Cytidine Monophosphate/metabolism , Enzyme Inhibitors/chemistry , Fluorescence Polarization , Fluorescent Dyes/metabolism , Kinetics , Molecular Docking Simulation , Neuraminic Acids/chemistry , Neuraminic Acids/metabolism , Pasteurella multocida/enzymology , Photobacterium/enzymology , Protein Binding , Protein Structure, Tertiary , Sialic Acids/metabolism , Sialyltransferases/antagonists & inhibitors , Substrate Specificity
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