Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.

Abstract

Fibrosis is an underlying cause of cirrhosis and hepatic failure resulting in end stage liver disease with limited pharmacological options. The beneficial effects of relaxin peptide treatment were demonstrated in clinically relevant animal models of liver fibrosis. However, the use of relaxin is problematic because of a short half-life. The aim of this study was to test the therapeutic effects of recently identified small molecule agonists of the human relaxin receptor, relaxin family peptide receptor 1 (RXFP1). The lead compound of this series, ML290, was selected based on its effects on the expression of fibrosis-related genes in primary human stellate cells. RNA sequencing analysis of TGF-β1-activated LX-2 cells showed that ML290 treatment primarily affected extracellular matrix remodeling and cytokine signaling, with expression profiles indicating an antifibrotic effect of ML290. ML290 treatment in human liver organoids with LPS-induced fibrotic phenotype resulted in a significant reduction of type I collagen. The pharmacokinetics of ML290 in mice demonstrated its high stability in vivo, as evidenced by the sustained concentrations of compound in the liver. In mice expressing human RXFP1 gene treated with carbon tetrachloride, ML290 significantly reduced collagen content, α-smooth muscle actin expression, and cell proliferation around portal ducts. In conclusion, ML290 demonstrated antifibrotic effects in liver fibrosis.-Kaftanovskaya, E. M., Ng, H. H., Soula, M., Rivas, B., Myhr, C., Ho, B. A., Cervantes, B. A., Shupe, T. D., Devarasetty, M., Hu, X., Xu, X., Patnaik, S., Wilson, K. J., Barnaeva, E., Ferrer, M., Southall, N. T., Marugan, J. J., Bishop, C. E., Agoulnik, I. U., Agoulnik, A. I. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.

• Authors: Elena M Kaftanovskaya, Hooi Hooi Ng, Mariluz Soula, Bryan Rivas, Courtney Myhr, Brian A Ho, Briana A Cervantes, Thomas D Shupe, Mahesh Devarasetty, Xin Hu, Xin Xu, Samarjit Patnaik, Kenneth J Wilson, Elena Barnaeva, Marc Ferrer, Noel T Southall, Juan J Marugan, Colin E Bishop, Irina U Agoulnik, Alexander I Agoulnik
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 11 Pg. 12435-12446 (11 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31419161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• RXFP1 protein, human
• Receptors, G-Protein-Coupled
• Receptors, Peptide

Topics

• Animals
• Carbon Tetrachloride Poisoning (drug therapy, genetics)
• Cell Line, Transformed
• Cell Proliferation (drug effects, genetics)
• Cytokines (genetics, metabolism)
• Humans
• Liver Cirrhosis (chemically induced, drug therapy, genetics, metabolism)
• Mice
• Mice, Transgenic
• Organoids (metabolism, pathology)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, genetics, metabolism)
• Receptors, Peptide (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects, genetics)