Structural and Functional Aspects of RGD-Containing Cyclic Pentapeptides as Highly Potent and Selective Integrin αVβ3 Antagonists

TLDR: The design of low-molecular-mass αVβ3 antagonists by “spatial screening” led to the highly active peptides c( RGDFV) and c(RGDFV), and the influence of the amino acids in positions 4 and 5 flanking the RGD-sequence on the inhibition of vitronectin and fibrinogen binding to the isolated αV β3 and αIIbβ3 receptors was investigated.

Abstract: The αVβ3 integrin is implicated in human tumor metastasis and in angiogenesis. The design of low-molecular-mass αVβ3 antagonists by “spatial screening” led to the highly active peptides c(RGDFV) and c(RGDFV). Here the influence of the amino acids in positions 4 and 5 flanking the RGD-sequence on the inhibition of vitronectin and fibrinogen binding to the isolated αVβ3 and αIIbβ3 receptors was investigated. The influence of the side chain and the backbone conformation on activity and selectivity was studied. The compounds were divided into conformational classes. For each class at least one representative peptide was subjected to detailed structure determination in solution. The peptides of classes 1, 2, and 3 show a βII‘/γ-turn arrangement with the d-amino acid in the i + 1 position of the βII‘-turn. By contrast, the peptides of class 4 reveal a modified βII‘/γ-turn pattern with glycine in the i + 1 position of the βII‘-turn and the d-amino acid in the i + 1 position of the γ-turn. Class 1 is divided into...