Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin[alpha]v[beta]3

A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin[alpha]v[beta]3 is based on two concepts: a)screening of systematically designed libraries with spatial diversity and b)masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1)initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5); 2)selection of cyclic peptides with the highest intestinal permeability; 3)design of sublibraries with the bioactive RGD sequence in all possible positions; 4)selection of the best ligands for RGD-recognizing integrin subtypes; 5)fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6)protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7)proof of biological effects in mice after oral administration.