Development of a single-chain peptide agonist of the relaxin-3 receptor using hydrocarbon stapling

K Hojo; MA Hossain; J Tailhades; F Shabanpoor; LLL Wong; EEK Ong-Pålsson; HE Kastman; S Ma; AL Gundlach; KJ Rosengren; JD Wade; RAD Bathgate

Journal article

Development of a single-chain peptide agonist of the relaxin-3 receptor using hydrocarbon stapling

K Hojo, MA Hossain, J Tailhades, F Shabanpoor, LLL Wong, EEK Ong-Pålsson, HE Kastman, S Ma, AL Gundlach, KJ Rosengren, JD Wade, RAD Bathgate

Journal of Medicinal Chemistry | AMER CHEMICAL SOC | Published : 2016

DOI: 10.1021/acs.jmedchem.6b00265

Abstract

Structure-activity studies of the insulin superfamily member, relaxin-3, have shown that its G protein-coupled receptor (RXFP3) binding site is contained within its central B-chain α-helix and this helical structure is essential for receptor activation. We sought to develop a single B-chain mimetic that retained agonist activity. This was achieved by use of solid phase peptide synthesis together with on-resin ruthenium-catalyzed ring closure metathesis of a pair of judiciously placed i,i+4 α-methyl, α-alkenyl amino acids. The resulting hydrocarbon stapled peptide was shown by solution NMR spectroscopy to mimic the native helical conformation of relaxin-3 and to possess potent RXFP3 receptor ..

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University of Melbourne Researchers

Akhter Hossain Author

Ross Bathgate Author

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Grants

Awarded by Naito Foundation

Funding Acknowledgements

This research was partly funded by NHMRC (Australia) project grants (508995) to J.D.W. and R.A.D.B. and (1065481 and 1066369) to R.A.D.B., K.J.R, and A.L.G. This research was also funded by The Naito Foundation (Japan) Subsidy for Female Researchers to K.H. We are grateful to Tania Ferraro and Sharon Layfield for assistance with cell-based assays and to Feng Lin for amino acid analysis. We thank Prof. Andrea Robinson and Dr. Alessia Belgi (Monash University, Australia) for assistance with the RCM reactions. During these studies, M.A.H. was the recipient of a Florey Foundation Fellowship. A.L.G. and R.A.D.B. are NHMRC Senior Research Fellows, and J.D.W. is an NHMRC Principal Research Fellow. K.J.R is an Australian Research Council Future Fellow. Studies at the Florey were supported by the Victorian Government's Operational Infrastructure Support Program.