Distance-Dependent Cellular Uptake of Oligoproline-Based Homobivalent Ligands Targeting GPCRs—An Experimental and Computational Analysis
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2020-10-21
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Journal Article
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Abstract
Tumor targeting with bivalent radiolabeled ligands for GPCRs is an attractive means for cancer imaging and therapy. Here, we studied and compared the distance dependence of homobivalent ligands for the human gastrin-releasing peptide receptor (hGRP-R) and the somatostatin receptor subtype II (hSstR2a). Oligoprolines were utilized as molecular scaffolds to enable distances of 10, 20, or 30 Å between two identical, agonistic recognition motifs. In vitro internalization assays revealed that ligands with a distance of 20 Å between the recognition motifs exhibit the highest cellular uptake in both ligand series. Structural modeling and molecular dynamics simulations support an optimal distance of 20 Å for accommodating ligand binding to both binding sites of a GPCR dimer. Translation of these findings to the significantly higher complexity in vivo proved difficult and showed only for the hGRP-R increased tumor uptake of the bivalent ligand. © 2020 American Chemical Society.
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published
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31 (10)
Pages / Article No.
2431 - 2438
Publisher
American Chemical Society
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03940 - Wennemers, Helma / Wennemers, Helma
03940 - Wennemers, Helma / Wennemers, Helma
03688 - Schibli, Roger / Schibli, Roger
03688 - Schibli, Roger / Schibli, Roger
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Funding
160805 - Targeting Cancer Cells with Hybrid and Heterovalent Ligands at Controlled Distances (SNF)