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High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4
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 therapeu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Singapore
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608467/ https://www.ncbi.nlm.nih.gov/pubmed/32235863 http://dx.doi.org/10.1038/s41401-020-0390-x |
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author | Lin, Guang-yao Lin, Lin Cai, Xiao-qing Dai, An-tao Zhu, Yue Li, Jie Liu, Qing Yang, De-hua Bathgate, Ross A. D. Wang, Ming-wei |
author_facet | Lin, Guang-yao Lin, Lin Cai, Xiao-qing Dai, An-tao Zhu, Yue Li, Jie Liu, Qing Yang, De-hua Bathgate, Ross A. D. Wang, Ming-wei |
author_sort | Lin, Guang-yao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7608467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-76084672020-11-05 High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 Lin, Guang-yao Lin, Lin Cai, Xiao-qing Dai, An-tao Zhu, Yue Li, Jie Liu, Qing Yang, De-hua Bathgate, Ross A. D. Wang, Ming-wei Acta Pharmacol Sin Article 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. Springer Singapore 2020-03-31 2020-10 /pmc/articles/PMC7608467/ /pubmed/32235863 http://dx.doi.org/10.1038/s41401-020-0390-x Text en © CPS and SIMM 2020 |
spellingShingle | Article Lin, Guang-yao Lin, Lin Cai, Xiao-qing Dai, An-tao Zhu, Yue Li, Jie Liu, Qing Yang, De-hua Bathgate, Ross A. D. Wang, Ming-wei High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
title | High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
title_full | High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
title_fullStr | High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
title_full_unstemmed | High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
title_short | High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
title_sort | high-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608467/ https://www.ncbi.nlm.nih.gov/pubmed/32235863 http://dx.doi.org/10.1038/s41401-020-0390-x |
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