Glycobiology vol 7 no 1 pp. 79-93, 1997
© 1997
research-article |
Selectin inhibition: synthesis and evaluation of novel sialylated, sulfated and fucosylated oligosaccharides, including the major capping group of GlyCAM-1
Glycobiology Program, UCSD Cancer Center, and the Division of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92903, USA
3The contributions of the first two authors should be considered equivalent
1Gynecologic Oncology Research, Roswell Park Cancer Institute Buffalo, NY 14263, USA
2To whom correspondence should be addressed at: Cancer Center, 0687, UCSD School of Medicine, La Jolla, CA 92093-0687
Received on June 12, 1996; revised on August 1, 1996; accepted on August 11, 1996
Selectins interact with glycoconjugate ligands in important normal and pathological situations. While high affinity recognition of natural ligands is associated with 
1–3(4)fucosylated, 2–3sialylated (and/or sulfated) lactosamine sequences, small oligosaccharides that potently inhibit the selectins have not been found. One possibility suggested by other investigators is that high affinity may require unusual sequences not yet tested, for example, the "major capping group" (6'-sulfo-sialyl Lex) of the L-selectin ligand GlyCAM-1. To explore this possibility, we synthesized a spectrum of novel synthetic and semisynthetic oligosaccharides related to those on natural ligands. In studying these molecules, we noted that binding of recombinant soluble selectins to immobilized sialyl Lex or 3'sulfo-Lex is markedly inhibited by concentrations of chloride above the physiological range. This indicates the ionic nature of the interactions, and shows that buffers typically used in screening assays for inhibitors are not optimal. Using parameters that more closely approximate physiological conditions, we confirmed that 2–3-linked sialic acids, and 1–3(4)fucosylation are important for recognition. Similar results obtained with both types of immobilized targets for the three selectins indicated that the binding sites for sialic acid and sulfate are very close, or identical. While O-sulfate esters mostly improved L- and P-selectin recognition, effects depended upon their position and number. Furthermore, sulfation can also impart some "negative" specificity: the major capping group does not interact with E-selectin. The branched Core 2 sequence seemed to enhance L- and P-selectin binding, however, the best inhibitors still appeared to be sialyl Lex and 3'-sulfo-Lex, with the aglycone group of the latter affecting binding. Of particular note, the "major capping group" of GlyCAM-1 was not an unusually potent nor highly selective inhibitor of L-selectin, even when studying the interaction of L-selectin with native GlyCAM-1 itself.
lectins structure binding ELISA
4Present address: Trans Cell Technology Inc., Monmouth Junction, NJ 08852, USA
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