Polysulfated derivatives of beta-cyclodextrin and myo-inositol as potent inhibitors of the interaction between L-selectin and peripheral addressin: implying a requirement for highly clustered sulfate groups.
We have utilized an in vitro assay that measures the binding of an L-selectin-human Fc chimera (LS-Fc) to [35S]sulfate labelled peripheral addressin (PNAd), a 120 kDa glycoprotein ligand for L-selectin in porcine lymph nodes, to evaluate inhibitory properties of a small group of sulfated derivatives of beta-cyclodextrin (beta-CD), sLe(x) and myo-inositol to their non-sulfated counterparts were studied. We found that hepta-sulfated beta-CD (IC50 = 0.2 mM) strongly inhibited the binding of L-selectin to PNAd. In contrast, the monosulfated beta-CD was a poor inhibitor, displaying < 10% inhibition at 0.5 mM and beta-CD was not active as an inhibitor. Similarly, inositol hexakissulfate, a compound containing six sulfate groups on the inositol ring displayed an inhibition of about 61% at 0.5 mM concentration, whereas the non-sulfated myoinositol was not inhibitory. These findings provide evidence that clustering of sulfate groups enhances affinity of molecules for binding to L-selectin.
Shailubhai
K
K
Department of Immunology, G.D. Searle Co., St. Louis, Missouri 63167, USA. KKSHAI@ccmail.monsanto.com
Abbas
S Z
SZ
Jacob
G S
GS
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019041:L-Selectin / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins; D009924:Organ Culture Techniques; D011485:Protein Binding; D013464:Sulfuric Acids / Q000737:chemistry*; D013552:Swine; D047392:beta-Cyclodextrins
D000954:Antigens, Surface; D003505:Cyclodextrins; C069886:L-selectin counter-receptors; D008565:Membrane Proteins; D013464:Sulfuric Acids; D047392:beta-Cyclodextrins; D019041:L-Selectin; D007294:Inositol; C031215:betadex