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

Hossain, M, Kocan, M, Yao, S, Royce, S, Nair, V, Siwek, C, Patil, N, Harrison, I, Rosengren, K, Selemidis, S, Summers, R, Wade, J, Bathgate, R and Samuel, C 2016, 'A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1', Chemical Science, vol. 7, no. 6, pp. 3805-3819.


Document type: Journal Article
Collection: Journal Articles

Title A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1
Author(s) Hossain, M
Kocan, M
Yao, S
Royce, S
Nair, V
Siwek, C
Patil, N
Harrison, I
Rosengren, K
Selemidis, S
Summers, R
Wade, J
Bathgate, R
Samuel, C
Year 2016
Journal name Chemical Science
Volume number 7
Issue number 6
Start page 3805
End page 3819
Total pages 15
Publisher Royal Society of Chemistry
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.
Subject Basic Pharmacology
Keyword(s) Chains
Chemical activation
Enzyme activity
Enzymes
Insulin
Molecular interactions
Peptides
Proteins
Tumors
DOI - identifier 10.1039/c5sc04754d
Copyright notice © The Royal Society of Chemistry 2016.
ISSN 2041-6520
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 26 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 7 times in Scopus Article | Citations
Altmetric details:
Access Statistics: 69 Abstract Views  -  Detailed Statistics
Created: Mon, 04 Dec 2017, 10:30:00 EST by Catalyst Administrator
© 2014 RMIT Research Repository • Powered by Fez SoftwareContact us