Structural and Functional Aspects of RGD-Containing Cyclic Pentapeptides as Highly Potent and Selective Integrin α_Vβ₃Antagonists

Abstract

The R V β 3 integrin is implicated in human tumor metastasis and in angiogenesis. The design of lowmolecular-mass R V β 3 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 R V β 3 and R IIb β 3 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 two subclasses: besides the βII′/γ-turn arrangement a γ/γ-turn motif is found for two members of this class. Structure-activity relationship (SAR) investigations show that the amino acid in position 4 and the proton of the amide bond between residues 3 and 4 are essential for high biological activities toward R V β 3 . By contrast, the amino acid in position 5 has no influence on the activity. A bent conformation of the RGD-sequence, as observed for the peptides of classes 1 and 2, fits the R V β 3 better than the R IIb β 3 receptor and so increases the selectivity of these peptides.

RGD‐containing trypsin with both platelet aggregation inhibitory activity and proteolytic activity

“…As RGD-containing proteins or peptides modeled after the RGD binding sequence on the fibrinogen alpha-chain could block the platelet glycoprotein IIb/llla, a receptor for fibrinogen, and effectively inhibit aggregation, they might be useful for treatment of thrombotic diseases [1][2][3][4][5].…”

“…To study the functional conformation of the RGD motif, native RGD-containing proteins, synthetic peptides as well as engineered proteins have been employed [2][3][4][5]. It was proposed that high flexibility of RGD motif region is critical to its function and conformational constraint is also important for the functional roles of RGD motif [1][2][3][4][5].…”

Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions

“…cRGD peptide selectively recognizes a v b 3 and a v b 5 integrins, 27 and previous studies showed that a v b 3 and a v b 5 are abundantly expressed on endothelial cells and smooth muscle cells in vascular lesions. [28][29][30] PEG-PAsp(DET) micelles installed with cRGD (cRGD-PEG-PAsp (DET) micelles) were applied to endothelial cells and vascular smooth muscle cells in vitro and also to rat carotid artery with neointimal hyperplasia, and the efficacy of gene transfer was evaluated as compared with that of ligand-free PEG-PAsp(DET) micelles.…”

Linking applicatory functions to the 3-position of pyrrole by click chemistry

“…27 For covalent linking of such cyclopeptides, modified or unmodified -amino lysine side chains were often used. [28][29][30][31][32] Recently Cu-catalyzed click reaction was performed at such a RGD-containing cyclopeptide wherein prior the lysine amino group was transferred into an azido group. 30 In another way the lysine amino group was acylated by propiolic acid and used to introduce an RGD-cyclopeptide into xylose by click chemistry.…”