Multivalent cyclic RGD ligands: influence of linker lengths on receptor binding
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 avidit...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
24 July 2010
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| In: |
Nuclear medicine and biology
Year: 2010, Volume: 37, Issue: 8, Pages: 885-891 |
| ISSN: | 1872-9614 |
| DOI: | 10.1016/j.nucmedbio.2010.06.005 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.nucmedbio.2010.06.005 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0969805110003112 
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| Author Notes: | Holger Kubas, Martin Schäfer, Ulrike Bauder-Wüst, Matthias Eder, Dörte Oltmanns, Uwe Haberkorn, Walter Mier, Michael Eisenhut |
| Summary: | 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 αvβ3 integrin significantly. The multivalent RGD peptides exhibited rather loose linkages partly including oligo(ethylene glycol) spacers (EGn) with different chain lengths. Therefore, the dependence of multivalent RGD systems with and without EGn linkers were investigated on their binding properties to cultured αvβ3 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 125I-labeled echistatin. - Results - While c(RGDyK) function is a relative weak competitor against [125I]echistatin (Ki, 329±18 nM) for αvβ3 integrin-expressing U87MG cells, RGD dimers improved the competition potency considerably (Ki, 64±23 nM). This effect was even more pronounced with the RGD trimers (Ki, 40±7 nM) and tetramers (Ki, 26±9 nM). The introduction of EGn spacers and the increase of linker lengths proved to be detrimental since more competitors were needed to compete with [125I]echistatin. The EG6 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 [125I]echistatin with the introduction of EGn spacers. This effect may be related to the decrease of the effective RGD molarity, which becomes most prominent within the tetravalent series. |
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| Item Description: | Gesehen am 07.03.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1872-9614 |
| DOI: | 10.1016/j.nucmedbio.2010.06.005 |