期刊
CHEMICAL SCIENCE
卷 7, 期 6, 页码 3805-3819出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5sc04754d
关键词
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资金
- National Health & Medical Research Council (NHMRC) of Australia [GNT1023321, GNT1023078, GNT1065481, GNT1050268, GNT1079680]
- NHMRC [GNT1055134, GNT5018148, GNT1042650, GNT1041766]
- ARC [LP110100288]
- Florey Foundation
- Melbourne Research Grant Support Scheme (RGSS)
- University of Melbourne
- Australian Postgraduate Award
- Australian Future Fellowships [FT130100890, FT120100876]
- Victorian Government Operational Infrastructure Support Program
- Australian Research Council [LP110100288] Funding Source: Australian Research Council
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.
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