The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Acta Pharmacol Sin. 2020 Oct;41(10):1328-1336. doi: 10.1038/s41401-020-0390-x. Epub 2020 Mar 31.
Relaxin/insulin-like family peptide receptor 4 (RXFP4) is a class A G protein-coupled receptor (GPCR), and insulin-like peptide 5 (INSL5) is its endogenous ligand. Although the precise physiological role of INSL5/RXFP4 remains elusive, a number of studies have suggested it to be a potential therapeutic target for obesity and other metabolic disorders. Since selective agonists of RXFP4 are scarcely available and peptidic analogs of INSL5 are hard to make, we conducted a high-throughput screening campaign against 52,000 synthetic and natural compounds targeting RXFP4. Of the 109 initial hits discovered, only 3 compounds were confirmed in secondary screening, with JK0621-D008 displaying the best agonism at human RXFP4. Its S-configuration stereoisomer (JK1) was subsequently isolated and validated by a series of bioassays, demonstrating a consistent agonistic effect in cells overexpressing RXFP4. This scaffold may provide a valuable tool to further explore the biological functions of RXFP4.
松弛素/胰岛素样家族肽受体 4（RXFP4）是一种 A 类 G 蛋白偶联受体（GPCR），胰岛素样肽 5（INSL5）是其内源性配体。尽管 INSL5/RXFP4 的精确生理作用仍不清楚，但许多研究表明它可能是肥胖症和其他代谢紊乱的潜在治疗靶点。由于选择性 RXFP4 激动剂稀缺，并且 INSL5 的肽类似物难以合成，我们针对 RXFP4 进行了针对 52000 种合成和天然化合物的高通量筛选活动。在发现的 109 个初始命中物中，只有 3 种化合物在二次筛选中得到确认，其中 JK0621-D008 在人 RXFP4 上显示出最佳激动作用。其 S-构型立体异构体（JK1）随后通过一系列生物测定法被分离和验证，在过表达 RXFP4 的细胞中表现出一致的激动作用。该支架可能为进一步探索 RXFP4 的生物学功能提供了有价值的工具。
