Conformational Constraints: Nature Does It Best with Sialyl Lewisx

Selectins play a key role in the inflammatory cascade. The interaction with their physiological ligands containing the tetrasaccharide sialyl Lewisx (sLex) leads to the recruitment of leukocytes from the vascular system to the site of injury. To facilitate the interaction under the shear stress conditions present in the blood vessel, the conformation of sLex is stabilized via lipophilic inter-residual contacts. sLex and two analogs were synthesized and evaluated for selectin binding, average conformation, and conformational dynamics. We could show that the methyl group in L-fucose is optimally suited to stabilize the sLex core through an interaction with the beta-face of D-galactose and thus enables binding to the selectins under shear stress conditions.