Probing the carbohydrate recognition domain of E-selectin: the importance of the acid orientation in sLex mimetics.
The selectin-leukocyte interaction is the initial event in the early inflammatory cascade. This interplay proceeds via the terminal tetrasaccharide sialyl Lewis(x) (sLe(x)), present on physiological selectin ligands and E- and P-selectins located on the endothelial surface. Blocking this process is regarded as a promising therapeutic approach for inflammatory diseases where excessive leukocyte efflux is responsible for tissue damage. Selectin antagonists are generally based on sLe(x) as lead structure, containing the essential pharmacophores pre-oriented in the bioactive conformation. In this work, we describe a set of competitive sLe(x) mimetics possessing the carboxylic acid pharmacophore equipped with additional hydrophobic substituents as neuraminic acid (Neu5Ac) replacements. This small library of antagonists derived from Huisgen-1,3-dipolar cycloadditions allows to further probe the carbohydrate recognition domain of E-selectin.
Titz
Alexander
A
Institute of Molecular Pharmacy, University of Basel, CH-4056 Basel, Switzerland.
Patton
John
J
Smiesko
Martin
M
Radic
Zorana
Z
Schwardt
Oliver
O
Magnani
John L
JL
Ernst
Beat
B
D001665:Binding Sites; D032701:Biomimetics; D019040:E-Selectin / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000080506:Sialyl Lewis X Antigen
D019040:E-Selectin; D008024:Ligands; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D012694:Serine; C072421:isoserine