Ligand interactions with E-selectin. Identification of a new binding site for recognition of N-acyl aromatic glucosamine substituents of sialyl Lewis X.
Several N-acylglucosamine derivatives of sialyl Lewis X (1-3) were prepared using a combined chemical enzymatic approach and evaluated as an inhibitor of E-selectin-mediated cellular adhesion. Compounds with aromatic functionality, 1 and 2, were found to be 3-10 times more potent than the N-acetyl derivative (14) in an ELISA E-selectin cell adhesion assay. Conformational analysis with NMR indicated that the sialyl Lewis x domain of 1 retained the conformation of the N-acetyl derivative (14) despite the presence of the N-naphthamido group. The dramatic order of magnitude increase in potency of these monovalent structures can be utilized to design more potent selectin-based cell adhesion inhibitors.
Ramphal
J Y
JY
Cytel Corporation, San Diego, California 92121, USA.
Hiroshige
M
M
Lou
B
B
Gaudino
J J
JJ
Hayashi
M
M
Chen
S M
SM
Chiang
L C
LC
Gaeta
F C
FC
DeFrees
S A
SA
D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000187:drug effects*; D019040:E-Selectin / Q000378:metabolism*; D005944:Glucosamine / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007983:Lewis Blood Group Antigens; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000080506:Sialyl Lewis X Antigen
D019040:E-Selectin; D007983:Lewis Blood Group Antigens; D008024:Ligands; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D005944:Glucosamine