Mimetics of Sialyl Lewisx: The Pre-Organization of the Carboxylic Acid is Essential for Binding to Selectins

Abstract

Selectins play a key role in leukocyte trafficking during the inflammatory response of the organism, i.e. the recruitment and extravasation of leukocytes from the blood stream into inflamed tissue. Antagonizing the interaction of selectins with their physiological ligands was shown to be a validated approach for the treatment of inflammatory disorders like rheumatoid arthritis, stroke or reperfusion injuries. Although numerous research efforts to identify small molecule selectin antagonists have been reported, no successful drug has been identified so far. This mini-review describes selectin antagonists, where the N-acetylneuraminic acid moiety of the natural ligand sialyl Lewisx is replaced by mimetics containing the essential carboxylic acid function. The prerequisite of a pre-organization of the carboxylate in the bioactive conformation is discussed.