8r5m
E-selectin complexed with glycomimetic ligand DS0567
Structural highlights
FunctionLYAM2_HUMAN Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with PSGL1/SELPLG. May have a role in capillary morphogenesis.[1] Publication Abstract from PubMedThe selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewis(x) (sLe(x), 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-selectin can functionally bind sLe(x)-modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLe(x) and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLe(x) mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin. Analogues of the pan-selectin antagonist rivipansel (GMI-1070).,Wagner B, Smiesko M, Jakob RP, Muhlethaler T, Cramer J, Maier T, Rabbani S, Schwardt O, Ernst B Eur J Med Chem. 2024 Jun 5;272:116455. doi: 10.1016/j.ejmech.2024.116455. Epub , 2024 Apr 30. PMID:38728868[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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