Chemo-enzymatic synthesis of LacdiNAc dimers of varying length as novel galectin ligands

• Published in: Journal of molecular catalysis. B, Enzymatic Vol. 101; pp. 47 - 55
• Main Authors: Šimonová, Anna, Kupper, Christiane E., Böcker, Sophia, Müller, Alwina, Hofbauerová, Kateřina, Pelantová, Helena, Elling, Lothar, Křen, Vladimír, Bojarová, Pavla
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.03.2014; Elsevier
• Subjects: Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Fundamental and applied biological sciences. Psychology; Galactosyltransferase; Galectin; Glycobiology; Methods. Procedures. Technologies; Multivalency; Galectin; Galactosyltransferase; Multivalency; Glycobiology; Enzymatic synthesis; N-Acetyllactosaminide α-1,3-galactosyltransferase; Enzyme; Ligand; Transferases; Glycosyltransferases; Hexosyltransferases
• ISSN: 1381-1177; 1873-3158
• DOI: 10.1016/j.molcatb.2013.12.018

•Series of LacdiNAc dimers containing flexible alkyl linkers were prepared.•Human placental β1,4-Gal-transferase-1 Y284L mutant was used for LacDiNAc synthesis.•The compounds were confirmed as ligands for human galectin-3.•No significant binding was observed with human galectin-1.•Flexible alkyl linkers (C: n>6) improve the binding capacity of LacdiNAc ligands. A set of sixteen bivalent symmetrical and asymmetrical LacdiNAc dimers containing flexible alkyl linkers were efficiently synthesized by means of chemo-enzymatic synthesis, using the versatile potential of the Y284L mutant of human placental β1,4-galactosyltransferase-1. LacdiNAc was confirmed to be a specific ligand for human galectin-3 contrary to human galectin-1. The compounds were tested as ligands for human galectin-3 in competitive binding assays and compared to a monovalent LacdiNAc standard. Molecular modeling was performed to calculate approximate length of respective ligands and its relation to their inhibitory capacity. The best performance was observed in symmetrical compounds carrying two LacdiNAc units connected with a hydrophobic linker of sufficient length (alkyl chain n≥6). Here, the IC50 value was about three times lower than that of the monovalent standard. Our results propose that hydrophobicity directed by the alkyl chain length as well as the specificity and bivalency of the LacdiNAc contribute to the inhibition potential of these ligands. Though only slightly pronounced in this case, higher multivalency is a promising feature in the design of optimized ligands for galectin-3.