Inhibitory activity of monomeric and polymeric selectin ligands

The ability of tetrasaccharides (SiaLex, SiaLea, HSO(3)Lex), their conjugates with polyacrylamide (40 kDa), and several other monomeric and polymeric substances to block selectins has been compared with that of polysaccaride fucoidan. Two assay systems were used: one was constructed on the base of recombinant E-, P-, and L-selectins; the other was a rat model of peritoneal inflammation. IC50 values for the neoglycoconjugate SiaLea-PAA were 6, 40, and 85 mu M with the recombinant E-, P-, and L-selectins, respectively; all monomeric inhibitors were about two orders of magnitude weaker. PAA-conjugates, containing as a ligand tyrosine-o-sulfate in addition to one of the above mentioned oligosaccharides, were the most potent synthetic blockers. Compared with the most potent of the known inhibitors, fucoidan, bi-ligand glycoconjugate HSO(3)Lea-PAA-sTyr, displayed in vitro similar activity in blocking L-selectin, while its activity towards P-selectin was tell times lower. All the synthetic polymers tested were able Co inhibit neutrophil extravasation to inflammation site, acting in concentration about 10 mg/kg. Thus, the effect of SiaLex is considerably more effective in vivo than in vitro, whereas heavily charged fucoidan and bi-ligand neoglycoconjugate acted in converse manner.