Péraldi-Roux Sylvie, Bayle Morgane, M'Kadmi Céline, Damian Marjorie, Vaillé Justine, Fernandez Gimena, Cornejo Maria Paula, Marie Jacky, Banères Jean-Louis, Ben Haj Salah Khoubaib, Fehrentz Jean-Alain, Cantel Sonia, Perello Mario, Denoyelle Séverine, Oiry Catherine, Neasta Jérémie
IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France.
Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE) -Argentine Research Council (CONICET), Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata, La Plata, Buenos Aires, Argentina.
Biochem Pharmacol. 2022 Aug;202:115114. doi: 10.1016/j.bcp.2022.115114. Epub 2022 May 31.
The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that regulates essential physiological functions. In particular, activation of GHSR in response to its endogenous agonist ghrelin promotes food intake and blood glucose increase. Therefore, compounds aimed at blocking GHSR signaling constitute potential options against obesity-related metabolic disorders. We have previously developed potent ligands of GHSR based on a triazole scaffold. Here, we report a new 3,4,5-trisubstituted 1,2,4-triazole compound, named JMV 6616, that potently blocks GHSR activity in vitro and in vivo. Specifically, in HEK293T cells JMV 6616 behaves as an inverse agonist since it binds to GHSR and inhibits its ghrelin-independent signaling. Accordingly, using purified labeled GHSR assembled into lipid nanodiscs we found that JMV 6616 decreases GHSR-catalyzed G protein activation and stabilizes an inactive receptor conformation. Importantly, JMV 6616 also acts on native GHSR since it blocks the insulinostatic effect of ghrelin in pancreatic islets. In mice, JMV 6616 inhibits blood glucose-raising effects of ghrelin treatment and the orexigenic actions of acute ghrelin administration. Together, our data suggest that this triazole-derived modulator of GHSR holds promise to mitigate several pathological features associated with eating and metabolic disorders.
生长激素促分泌素受体（GHSR）是一种调节基本生理功能的G蛋白偶联受体。特别是，GHSR对内源性激动剂胃饥饿素的激活会促进食物摄入和血糖升高。因此，旨在阻断GHSR信号传导的化合物构成了对抗肥胖相关代谢紊乱的潜在选择。我们之前基于三唑支架开发了强效的GHSR配体。在此，我们报道了一种新的3,4,5-三取代1,2,4-三唑化合物，名为JMV 6616，它在体外和体内均能有效阻断GHSR活性。具体而言，在HEK293T细胞中，JMV 6616表现为反向激动剂，因为它与GHSR结合并抑制其非胃饥饿素依赖性信号传导。相应地，使用组装到脂质纳米盘的纯化标记GHSR，我们发现JMV 6616可降低GHSR催化的G蛋白激活，并稳定无活性的受体构象。重要的是，JMV 6616也作用于天然GHSR，因为它可阻断胃饥饿素在胰岛中的胰岛素稳定作用。在小鼠中，JMV 6616可抑制胃饥饿素治疗引起的血糖升高作用以及急性给予胃饥饿素后的促食欲作用。总之，我们的数据表明，这种源自三唑的GHSR调节剂有望减轻与饮食和代谢紊乱相关的几种病理特征。
