Cyclic RGD-Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds as New Potent Integrin Ligands

摘要

The tripeptide sequence arginine-glycine-aspartate(RGD) has been identified as the common motif used by several endogenous ligands to recognise and bind a group of integrins,[1] including aVb3, aVb5, a5b1, which play key roles in angiogenesis, tumor progression and metastasis.[2] The context of the ligand RGD sequence (flanking residues,three-dimensional presentation) and individual features of the integrin binding pockets determine the recognition specificity and discrimination ability, that is, whether a productive interaction occurs. A major breakthrough for understanding this interaction came in 2002 from the X-ray structure determination of the complex of integrin aVb3 with cyclo-[Arg-Gly-Asp-d-Phe-N(Me)-Val] (Cilengitide).[3] This potent aVb3 ligand was developed by Kessler and co-workers,[4] and is currently in phase III clinical trials for patients with glioblastoma multiforme as an angiogenesisis inhibitor.