Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1

F Shabanpoor; M Akhter Hossain; PJ Ryan; A Belgi; S Layfield; M Kocan; S Zhang; CS Samuel; AL Gundlach; RAD Bathgate; F Separovic; JD Wade

Journal article

Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1

F Shabanpoor, M Akhter Hossain, PJ Ryan, A Belgi, S Layfield, M Kocan, S Zhang, CS Samuel, AL Gundlach, RAD Bathgate, F Separovic, JD Wade

Journal of Medicinal Chemistry | Published : 2012

DOI: 10.1021/jm201505p

Abstract

Relaxin-3 is a neuropeptide that is implicated in the regulation of stress responses and memory. The elucidation of its precise physiological role(s) has, however, been hampered by cross-activation of the relaxin-2 receptor, RXFP1, in the brain. The current study undertook to develop analogues of human relaxin-3 (H3 relaxin) that can selectively bind and activate its receptor, RXFP3. We developed a high-affinity selective agonist (analogue 2) by removal of the intra-A chain disulfide bond and deletion of 10 residues from the N terminus of the A chain. Further truncation of this analogue from the C terminus of the B chain to CysB22 and addition of an ArgB23 led to a high-affinity, RXFP3-selec..

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University of Melbourne Researchers

Ross Bathgate Author

Frances Separovic Author

Akhter Hossain Author

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Grants

Awarded by NHMRC (Australia)

Funding Acknowledgements

This research was funded by NHMRC (Australia) project grants 350284, 508995 to J.D.W. and R.A.D.B., and 509246 to A.L.G. We are grateful to Tania Ferraro for assistance with biochemical assays and to Dr. Tony Hughes (Department of Pharmacology, The University of Melbourne) for valuable advice. During these studies, M.A.H. was the recipient of a Reid Trust Fellowship, and P.J.R was the recipient of a Commonwealth Australian Postgraduate Award and a Dowd Foundation Scholarship. J.D.W., R.A.D.B., and A.L.G. are NHMRC Research Fellows, and C.S.S. is an NHF Research Fellow. Studies at the FNI were supported by the Victorian Government's Operational Infrastructure Support Program.