The chemistry of oligosaccharide ligands of selectins: Significance for the development of new immunomodulatory medicines

Abstract

Publisher Summary This chapter provides a synoptic review of several investigations that have converged and synergistically interacted to develop clinically useful anti-inflammatory therapeutics from inhibitors of selectin–ligand interactions. The chapter presents a summary of early cell-physiological studies with monoclonal antibodies that led to the independent discoveries of endothelial (E), platelet (P), and leukocyte (L)-selectins in the fields of vascular physiology, platelet activation, and lymphocyte trafficking. The chapter also discusses the results of these investigations, important insights are provided on the cellular distribution and mode of expression of the selectins, and their roles in acute and chronic inflammation. Application of the methods of molecular genetics has led to the molecular characterization and expression cloning of the selectins. The typical domain structure of the selectins, most notably the N-terminal lectin domain with its high degree of homology, not only among the selectins but also with previously known, C-(Ca 2+ )-type mammalian lectins, such as liver lectin or mannose-binding proteins is presented. The chapter also discusses the structures of the carbohydrate determinants that would physiologically bind to the lectin domains of the selectins, leading to the identification of the common sialyl-Lewis x (sLe x ) tetrasaccharide motif.