Design and Chemical Synthesis of Integrin Ligands

The design and synthesis of peptidic and nonpeptidic integrin ligands derived from the most abundant natural tripeptide sequence, RGD, are described in this article. Special emphasis is placed on the activity and selectivity of the ligands to integrin subtypes. Two approaches are described—ligand‐ and structure‐oriented design. When no structure of the complex or the target is known, one may derive suitable starting points from natural peptide sequences, which often require conformational restriction for a further optimization. A "spatial screening" procedure was used to identify highly active and selective ligands for the integrin subtypes αvβ3 and αIIbβ3. Structure‐based methods require knowledge of the binding domain of the target. Hence, the first structure of the αvβ3 integrin with bound cilengitide was a landmark for the structure‐based approach. Meanwhile, a design using homology models of other integrin subtypes has also been successfully applied. To improve the ADME profile, nonpeptidic ligands have been developed using the information of the spatial distances and orientations of the most important pharmacophoric groups (especially the carboxyl group and the basic moiety at the other end of the molecule). Applications of the αvβ3 ligands as drugs in antiangiogenic tumor therapy for molecular imaging of metastases and for improvement of biocompatibility of grafts are briefly described.