Inhibition of cell adhesion to fibronectin by oligopeptide-substituted polynorbornenes

Polynorbornenes substituted with two different peptide sequences from the R GD-containing integrin cell-binding domain of fibronectin are potent inhibi tors of human foreskin fibroblast cell adhesion to fibronectin-coated surfa ces. Ring-opening metathesis polymerization (ROMP)using Ru=CHPh(Cl)(2)(PCy3 )(DHIMes) (1) as an initiator produced polymers substituted with GRGDS and PHSRN peptide sequences. The inhibitory activity was quantified for these p olymers and compared to the free peptides and GRGES-containing controls. A homopolymer substituted with GRGDS peptides was significantly more active t han the free GRGDS peptide (IC50 of 0.18 +/- 0.03 and 1.33 +/- 0.20 mM resp ectively), and the copolymer containing both GRGDS and PHSRN is the most po tent inhibitor (IC50 of 0.04 +/- 0.01 mM). These results demonstrate that s ignificant enhancements of observed biological activity can be obtained fro m polymeric materials containing more than one type of multivalent ligand a nd that ROMP is a-useful method to synthesize such well-defined copolymers.