The solution structures of trisaccharide inhibitors of selectin-mediated cell adhesion are being studied by NOESY and ROESY NMR spectroscopy. E- and P-selectin are multi-domain proteins expressed on vascular endothelial cell surfaces in response to tissue damage; their function is to induce leukocyte transient attachment and rolling by binding carbohydrates on the mobile cells' surfaces. These events are critical parts of the inflammatory immune response. L-selectin, on the leukocyte surface, binds to carbohydrates on endothelial cells as part of regular trafficking to the lymph. Afflictions such as rheumatoid arthritis and reperfusion injury are caused in large part by disruptions in the normal functioning of these systems. Minimal carbohydrate motifs that promote binding are related to the trisaccharides Lewisa (Fuc(()1-4[Gal(()1-3]Glc) and Lewisx (Fuc(()1-3[Gal(()1-4]Glc); charge has also been identified as an important factor in binding specificity and strength. To investigate the relationships between charge location on the trisaccharide units and binding strength, specificity, and mode, several sulfated derivatives of Lewisa and Lewisx have been synthesized. It is important to know what effects sulfation has on the carbohydrate structure in order to infer useful information about possible binding modes from binding data. To accomplish this end and the lay the groundwork for NMR studies on the selectin-carbohydrate complexes, the determination of the solution structures of Lewis a derivatives sulfated at the 3(-Gal, 6(-Gal, 3(-6(-Gal positions and phosphorylated at the 3(-Gal positions have been initiated. Similar studies are being undertaken with the Lewisx derivatives as they are made available.
Showing the most recent 10 out of 613 publications
