UNLABELLED: Peptides involving the RGD motive (arginine-glycine-aspartic acid) recognize members of the integrin receptor family. Since the receptors are located mainly on the surface of endothelial cells, structural modifications including multimers of c(RGDfE) were recently found to improve the binding avidity for α(v)β(3) integrin significantly. The multivalent RGD peptides exhibited rather loose linkages partly including oligo(ethylene glycol) spacers (EG(n)) with different chain lengths. Therefore, the dependence of multivalent RGD systems with and without EG(n) linkers were investigated on their binding properties to cultured α(v)β(3) integrin-expressing U87MG cells. METHODS: We synthesized a series of di-, tri- and tetravalent rigid scaffolds (terephthalic acid, trimesic acid and adamantane-1,3,5,7-tetracarboxylic acid) conjugated to c(RGDyK) ligands, which were linked contiguously or separated by the oligo(ethylene glycol) spacers. The inhibition constants of these c(RGDyK) derivatives were determined by competition assays with (125)I-labeled echistatin. RESULTS: While c(RGDyK) function is a relative weak competitor against [(125)I]echistatin (K(i), 329 ± 18 nM) for α(v)β(3) integrin-expressing U87MG cells, RGD dimers improved the competition potency considerably (K(i), 64 ± 23 nM). This effect was even more pronounced with the RGD trimers (K(i), 40 ± 7 nM) and tetramers (K(i), 26±9 nM). The introduction of EG(n) spacers and the increase of linker lengths proved to be detrimental since more competitors were needed to compete with [(125)I]echistatin. The EG(6) group, for example, reduced the inhibition constants by 29% (dimer), 57% (trimer) and 97% (tetramer). CONCLUSION: The binding experiments performed with the three forms of multivalent RGD ligands indicate the weakening of competitive potency against [(125)I]echistatin with the introduction of EG(n) spacers. This effect may be related to the decrease of the effective RGD molarity, which becomes most prominent within the tetravalent series.
UNLABELLED: Peptides involving the RGD motive (arginine-glycine-aspartic acid) recognize members of the integrin receptor family. Since the receptors are located mainly on the surface of endothelial cells, structural modifications including multimers of c(RGDfE) were recently found to improve the binding avidity for α(v)β(3) integrin significantly. The multivalent RGD peptides exhibited rather loose linkages partly including oligo(ethylene glycol) spacers (EG(n)) with different chain lengths. Therefore, the dependence of multivalent RGD systems with and without EG(n) linkers were investigated on their binding properties to cultured α(v)β(3) integrin-expressing U87MG cells. METHODS: We synthesized a series of di-, tri- and tetravalent rigid scaffolds (terephthalic acid, trimesic acid and adamantane-1,3,5,7-tetracarboxylic acid) conjugated to c(RGDyK) ligands, which were linked contiguously or separated by the oligo(ethylene glycol) spacers. The inhibition constants of these c(RGDyK) derivatives were determined by competition assays with (125)I-labeled echistatin. RESULTS: While c(RGDyK) function is a relative weak competitor against [(125)I]echistatin (K(i), 329 ± 18 nM) for α(v)β(3) integrin-expressing U87MG cells, RGD dimers improved the competition potency considerably (K(i), 64 ± 23 nM). This effect was even more pronounced with the RGD trimers (K(i), 40 ± 7 nM) and tetramers (K(i), 26±9 nM). The introduction of EG(n) spacers and the increase of linker lengths proved to be detrimental since more competitors were needed to compete with [(125)I]echistatin. The EG(6) group, for example, reduced the inhibition constants by 29% (dimer), 57% (trimer) and 97% (tetramer). CONCLUSION: The binding experiments performed with the three forms of multivalent RGD ligands indicate the weakening of competitive potency against [(125)I]echistatin with the introduction of EG(n) spacers. This effect may be related to the decrease of the effective RGD molarity, which becomes most prominent within the tetravalent series.
Authors: Job Boekhoven; Charles M Rubert Pérez; Shantanu Sur; Amanda Worthy; Samuel I Stupp Journal: Angew Chem Int Ed Engl Date: 2013-09-24 Impact factor: 15.336
Authors: Martin Schäfer; Ulrike Bauder-Wüst; Karin Leotta; Frederic Zoller; Walter Mier; Uwe Haberkorn; Michael Eisenhut; Matthias Eder Journal: EJNMMI Res Date: 2012-06-06 Impact factor: 3.138
Authors: Ethan A Englund; Deyun Wang; Hidetsugu Fujigaki; Hiroyasu Sakai; Christopher M Micklitsch; Rodolfo Ghirlando; Gema Martin-Manso; Michael L Pendrak; David D Roberts; Stewart R Durell; Daniel H Appella Journal: Nat Commun Date: 2012-01-10 Impact factor: 14.919
Authors: Diego Pallarola; Alexander Bochen; Heike Boehm; Florian Rechenmacher; Tariq R Sobahi; Joachim P Spatz; Horst Kessler Journal: Adv Funct Mater Date: 2013-10-16 Impact factor: 18.808