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

Hossain, Mohammed Akhter, Kocan, Martina, Yao, Song T., Royce, Simon G., Nair, Vinojini B., Siwek, Christopher, Patil, Nitin A., Harrison, Ian P., Rosengren, K. Johan, Selemidis, Stavros, Summers, Roger J., Wade, John D., Bathgate, Ross A. D. and Samuel, Chrishan S. (2016) A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1. Chemical Science, 7 6: 3805-3819. doi:10.1039/c5sc04754d

Author Hossain, Mohammed Akhter
Kocan, Martina
Yao, Song T.
Royce, Simon G.
Nair, Vinojini B.
Siwek, Christopher
Patil, Nitin A.
Harrison, Ian P.
Rosengren, K. Johan
Selemidis, Stavros
Summers, Roger J.
Wade, John D.
Bathgate, Ross A. D.
Samuel, Chrishan S.
Title A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1
Journal name Chemical Science   Check publisher's open access policy
ISSN 2041-6539
Publication date 2016-06-01
Year available 2016
Sub-type Article (original research)
DOI 10.1039/c5sc04754d
Open Access Status DOI
Volume 7
Issue 6
Start page 3805
End page 3819
Total pages 15
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Language eng
Formatted 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 prevented or reversed organ fibrosis and dysfunction in three pre-clinical rodent models of heart or lung disease with similar potency to H2 relaxin. The molecular mechanism behind the strong anti-fibrotic actions of B7-33 involved its activation of RXFP1-Angiotensin II type 2 receptor heterodimers that induced selective downstream signaling of pERK1/2 and the collagen-degrading enzyme, matrix metalloproteinase (MMP)-2. Furthermore, in contrast to H2 relaxin, B7-33 did not promote prostate tumor growth in vivo. Our results represent the first known example of the minimisation of a two-chain cyclic insulin-like peptide to a single-chain linear peptide that retains potent beneficial agonistic effects.
Keyword Relaxin
G protein-coupled receptor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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School of Biomedical Sciences Publications
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