期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：48
DOI：10.1073/pnas.2108776118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
G protein–coupled receptors (GPCRs) are major players in cellular signal transmission. In this work, we have used rigid oligoproline backbones derivatized with two ligands at defined distances to induce GPCR dimer formation as a way to alter its signaling profile. We show that bivalent ligands at distances of 20 and 30 Å induce dimers of the GRPR receptor with different signaling responses. In addition, a nondimer–inducing bivalent ligand (with 10-Å distance between agonists) also induces different signaling patterns, most likely due to allosteric effects. These findings identify bivalent ligands with a stiff oligoproline backbone as tools to explore the natural signaling space of GPCRs.
G protein–coupled receptors (GPCRs) are one of the most important drug–target classes in pharmaceutical industry. Their diversity in signaling, which can be modulated with drugs, permits the design of more effective and better-tolerated therapeutics. In this work, we have used rigid oligoproline backbones to generate bivalent ligands for the gastrin-releasing peptide receptor (GRPR) with a fixed distance between their recognition motifs. This allows the stabilization of GPCR dimers irrespective of their physiological occurrence and relevance, thus expanding the space for medicinal chemistry. Specifically, we observed that compounds presenting agonists or antagonists at 20- and 30-Å distance induce GRPR dimerization. Furthermore, we found that 1) compounds with two agonists at 20- and 30-Å distance that induce dimer formation show bias toward Gq efficacy, 2) dimers with 20- and 30-Å distance have different potencies toward β-arrestin-1 and β-arrestin-2, and 3) the divalent agonistic ligand with 10-Å distance specifically reduces Gq potency without affecting β-arrestin recruitment, pointing toward an allosteric effect. In summary, we show that rigid oligoproline backbones represent a tool to develop ligands with biased GPCR signaling.
