Assembly of P-Selectin Ligands on a Polymeric Template Original Research Article

High-affinity receptor-ligand interactions frequently involve molecular interactions at two distinct sites. A derivatized polyacrylic-based polymer was synthesized to allow substitution with multiple ligands (e.g., L1 and L2) on the backbone. Two-site P-selectin-ligand interactions were first studied with SiaLex (L1) and tyrosine sulfate (L2) covalently incorporated onto the flexible polymer. In competition assays, a marked synergistic inhibitory effect was observed when the polymer presented both L1 and L2 as opposed to either ligand alone. In a second approach, the SiaLeX ligand was reduced in complexity so that L1 was fixed as Lex or Lea, and alternative L2 groups (to mimic sialic acid) were investigated. Certain combinations of L1 and L2 were better antagonists of P-selectin than SiaLex itself. These approaches offer the potential of facilitating the discovery of novel inhibitors of receptors or enzymes.