Sialyl Lewis X mimics derived from a pharmacophore search are selectin inhibitors with anti-inflammatory activity.
The selectins, a family of adhesion receptors involved in leukocyte extravasation, recognize sialyl Lewis X (sLe(x); NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc) and related oligosaccharides. We used conformational energy computations, high field NMR, and structure-function studies to define distance parameters of critical functional groups of sLe(x). This sLe(x) pharmacophore was used to search a three-dimensional data base of chemical structures. Compounds that had a similar spatial relationship of functional groups were tested as inhibitors of selectin binding. Glycyrrhizin, a triterpene glycoside, was identified and found to block selectin binding to sLe(x) in vitro. We substituted different sugars for the glucuronic acids of glycyrrhizin and found the L-fucose derivative to be the most active in vitro and in vivo. A C-fucoside derivative, synthesized on a linker designed for stability and to more closely approximate the original sLe(x) pharmacophore, resulted in an easily synthesized, effective selectin blocker with anti-inflammatory activity.
Rao
B N
BN
Glycomed Inc., Alameda, California 94501.
Anderson
M B
MB
Musser
J H
JH
Gilbert
J H
JH
Schaefer
M E
ME
Foxall
C
C
Brandley
B K
BK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D015815:Cell Adhesion Molecules / Q000187:drug effects*; D019040:E-Selectin; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019695:Glycyrrhizic Acid; D019041:L-Selectin; D051379:Mice; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects; D011971:Receptors, Immunologic / Q000187:drug effects; D000080506:Sialyl Lewis X Antigen
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D009844:Oligosaccharides; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D011971:Receptors, Immunologic; D000080506:Sialyl Lewis X Antigen; D019041:L-Selectin; D019695:Glycyrrhizic Acid; D006034:Glycyrrhetinic Acid