A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1

Chemical Science
Mohammed A HossainChrishan S Samuel

Abstract

Human gene-2 relaxin (H2 relaxin) is a pleiotropic hormone with powerful vasodilatory and anti-fibrotic properties which has led to its clinical evaluation and provisional FDA approval as a treatment for acute heart failure. The diverse effects of H2 relaxin are mediated via its cognate G protein coupled-receptor (GPCR), Relaxin Family Peptide Receptor (RXFP1), leading to stimulation of a combination of cell signalling pathways that includes cyclic adenosine monophosphate (cAMP) and extracellular-signal-regulated kinases (ERK)1/2. However, its complex two-chain (A and B), disulfide-rich insulin-like structure is a limitation to its facile preparation, availability and affordability. Furthermore, its strong activation of cAMP signaling is likely responsible for reported detrimental tumor-promoting actions that may preclude long-term use of this drug for treating human disease. Here we report the design and synthesis of a H2 relaxin B-chain-only analogue, B7-33, which was shown to bind to RXFP1 and preferentially activate the pERK pathway over cAMP in cells that endogenously expressed RXFP1. Thus, B7-33 represents the first functionally selective agonist of the complex GPCR, RXFP1. Importantly, this small peptide agonist prevente...Continue Reading

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Citations

Aug 23, 2018·The Journal of Biological Chemistry·Linda M Haugaard-KedströmK Johan Rosengren
Sep 13, 2019·Journal of the American Society of Nephrology : JASN·Bryna S M ChowChrishan S Samuel
Feb 27, 2020·Molecular Genetics & Genomic Medicine·Ting-Yun ChenYingze Zhang
Apr 17, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chao WangChrishan S Samuel
May 29, 2018·Neurourology and Urodynamics·Youko IkedaAnthony J Kanai
Jun 6, 2018·Frontiers in Pharmacology·Hooi Hooi NgRebecca H Ritchie
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Dec 14, 2018·Bioconjugate Chemistry·Avinash MuppidiWeijun Shen
Nov 13, 2019·ACS Applied Materials & Interfaces·Nicholas G WelchHelmut Thissen

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Methods Mentioned

BETA
X-ray
NMR
AlphaScreen

Software Mentioned

GraphPad Prism
XEASY
Topspin
Image J
GraphPad

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