In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis
| Autor: | Sapna Desai, Danuta Ewa Irena Mossakowska, Scott P. Webster, Duncan S. Holmes, Andrew McBride, Jonathan A. Fallowfield, Kate Simpson, Martin P. Ruediger, Mark J. Bamford, Rebecca L. Aucott, Jeremy Griggs, John P. Iredale, Ivan Caballero-Hernandez, Anna M. Hoy, Theresa J. Pell |
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| Rok vydání: | 2017 |
| Předmět: |
Liver Cirrhosis
0301 basic medicine Agonist Allosteric modulator Receptors Peptide medicine.drug_class Biopsy Allosteric regulation Drug Evaluation Preclinical Druggability lcsh:Medicine Enzyme Activators Pharmacology Biology Article Receptors G-Protein-Coupled 03 medical and health sciences Drug Discovery Journal Article medicine Humans lcsh:Science Receptor Cells Cultured Relaxin Multidisciplinary lcsh:R High-Throughput Screening Assays 030104 developmental biology Hepatic stellate cell lcsh:Q Relaxin receptor |
| Zdroj: | McBride, A, Hoy, A M, Bamford, M J, Mossakowska, D E, Ruediger, M P, Griggs, J, Desai, S, Simpson, K, Caballero-Hernandez, I, Iredale, J P, Pell, T, Aucott, R L, Holmes, D S, Webster, S P & Fallowfield, J A 2017, ' In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis ', Scientific Reports, vol. 7, no. 1, pp. 10806 . https://doi.org/10.1038/s41598-017-10521-9 Scientific Reports Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-10521-9 |
| Popis: | The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery. |
| Databáze: | OpenAIRE |
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