A new concept for glycosyltransferase inhibitors: nonionic mimics of the nucleotide donor of the human blood group B galactosyltransferase.
Glycosyltransferases play an important role in the formation of oligosaccharides and glycoconjugates. To find suitable and selective inhibitors for this class of enzymes is still challenging. Here, we describe a novel concept that allows the design of inhibitors based on the structure of the donor substrate binding pocket. As a first step we describe the design, synthesis and analysis of inhibitors of the human blood group B galactosyltransferase (GTB). This enzyme served as a model system to study the concept, which can be used for easy access of glycosyltransferase inhibitors in general. In silico docking of bicyclic heteroaromatic ligands to GTB and experimental verification of binding affinities by saturation transfer difference NMR (STD NMR) spectroscopy gave 9-N-pentityl uric acid derivatives as non-ionic mimics of UDP. Two derivatives were synthesized and showed inhibitory activity for GTB as determined by competitive STD NMR experiments and by a radiolabeled enzyme assay.
Department of Chemistry, University of Hamburg, Organic Chemistry, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Katrin
K
Schaefer
Joachim
J
Albers
Nora
N
Sindhuwinata
Thomas
T
Peters
Bernd
B
Meyer
D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D014527:Uric Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014527:Uric Acid; D005700:Galactosyltransferases; C023155:blood-group-substance alpha-D-galactosyltransferase