Two highly homologous dimeric disintegrins, CC5 and CC8, have been isolated from the venom of the North African sand viper Cerastes cerastes. CC5 is a homodimer containing an RGD motif in its subunits. CC8 is a heterodimer. The CC8A and CC8B subunits contain RGD and WGD tripeptide sequence in their respective integrin-binding loops. Both CC5 and CC8 inhibited platelet aggregation and the adhesion of cells expressing integrins alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 to appropriate ligands. However, the inhibitory activity of CC8 was at least 1 order of magnitude higher than that of CC5. Enhanced activity of CC8 over CC5 was also observed in the induction of LIBS epitopes on beta1 and beta3 integrins. Synthetic peptides in which the arginyl residue of the RGD motif had been replaced with tryptophans exhibited increased inhibitory activity toward integrins alpha5beta1, alphaII(b)beta3, and alpha(v)beta3. Moreover, alanine substitution of the aspartic acid of the WGD motif of these peptides decreased their inhibitory ability, whereas the same substitution in the RGD sequence almost completely abolished the activity of the peptides. We conclude that the WGD motif enhances the inhibitory activity of disintegrins toward alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 integrins.