Distance-Dependent Cellular Uptake of Oligoproline-Based Homobivalent Ligands Targeting GPCRs—An Experimental and Computational Analysis,Bioconjugate Chemistry

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Distance-Dependent Cellular Uptake of Oligoproline-Based Homobivalent Ligands Targeting GPCRs—An Experimental and Computational Analysis
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-10-13 , DOI: 10.1021/acs.bioconjchem.0c00484
Stefanie Dobitz ₁ , Patrick Wilhelm ₁ , Nina Romantini ₂ , Martina De Foresta ₁ , Cornelia Walther ₂ , Andreas Ritler _{1,

2} , Roger Schibli _{2,

3} , Philipp Berger ₄ , Xavier Deupi ₄ , Martin Béhé ₂ , Helma Wennemers ₁

Affiliation

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 (hSstR_2a). 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.

中文翻译：

靶向GPCR的基于寡聚脯氨酸的同价二价配体的距离依赖性细胞摄取—实验和计算分析

用针对GPCR的二价放射性标记配体靶向肿瘤是癌症成像和治疗的一种有吸引力的方法。在这里，我们研究并比较了人类胃泌素释放肽受体（hGRP-R）和生长抑素受体亚型II（hSstR _2a）的同二价配体的距离依赖性）。寡脯氨酸被用作分子支架，以使两个相同的激动性识别基序之间的距离为10、20或30。体外内化分析表明，识别基序之间的距离为20Å的配体在两个配体系列中均显示出最高的细胞吸收率。结构建模和分子动力学模拟支持20Å的最佳距离，以适应配体与GPCR二聚体两个结合位点的结合。将这些发现转化为体内明显更高的复杂性证明是困难的，并且仅显示出hGRP-R增加了二价配体的肿瘤摄取。

更新日期：2020-10-21

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