A combinatorial approach is proposed as a general method for elucidating the receptor-bound conformation of peptide ligands. A library of template-constrained cyclic peptides incorporating bis-ureas will be synthesized. These cyclic peptides will serve to present the same recognition elements in different conformations. The library will be screened for high affinity binding to the RGD-binding integrins (alpha5beta1, alphaIIbbeta3, and alphaVbeta3). Subsequent structural analysis of the high binding affinity peptidomimetics will enable the elucidation of the integrin-bound conformations which are useful for the development of relevant therapeutic drugs. This general approach involving libraries of template-constrained cyclic peptides can be applied to any receptor with a short peptidyl ligand.
