Engineering of a Novel Simplified Human Insulin-Like Peptide 5 Agonist

NA Patil; RA Hughes; KJ Rosengren; M Kocan; SY Ang; J Tailhades; F Separovic; RJ Summers; J Grosse; JD Wade; RAD Bathgate; MA Hossain

Journal article

Engineering of a Novel Simplified Human Insulin-Like Peptide 5 Agonist

NA Patil, RA Hughes, KJ Rosengren, M Kocan, SY Ang, J Tailhades, F Separovic, RJ Summers, J Grosse, JD Wade, RAD Bathgate, MA Hossain

Journal of Medicinal Chemistry | Published : 2016

DOI: 10.1021/acs.jmedchem.5b01786

Abstract

© 2016 American Chemical Society. Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SARs) of INSL5 and use it to develop a potent and simpler INSL5 mimetic with RXFP4 agonist activity. A series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically synthesized, resulting in a chimeric INSL5 analogue exhibiting more than 10-fold higher potency (0.35 nM) at human RXFP4 compared with native hINSL5 (4.57..

View full abstract

University of Melbourne Researchers

Frances Separovic Author

Ross Bathgate Author

Akhter Hossain Author

Related Projects (3)

INTERROGATING PEPTIDE RECEPTOR TARGETS

The neuropeptide relaxin-3 and the peptide hormone INSL5 are recently discovered members of the relaxin peptide family. Relaxin-3 has import..

Novel insulin to treat diabetes

The glucose regulatory hormone, insulin, remains the only treatment for type I diabetes and up to 30% of type II diabetes, both of which are..

Enhancing the clinical potential of relaxin

The hormone relaxin mediates cardiovascular and kidney changes during pregnancy. These important functions have led to its current use in cl..

Grants

Awarded by Australian Research Council

Funding Acknowledgements

This research was partly funded by NHMRC (Australia) project grants (1023321, 1065481, and 1023078) to M.A.H., R.A.D.B., J.K.R., and J.D.W., and ARC linkage grant (LP120100654) to R.A.H. K.J.R. is an Australian Research Council Future Fellow (FT130100890). R.J.S. and M.K. funded by NHMRC Program Grant 1055134 to R.J.S. and S.Y.A. by a Monash Graduate Scholarship and Monash International Postgraduate Research Scholarship. We are grateful to Tania Ferraro and Sharon Layfield for assistance with biochemical assays and to Feng Lin for amino acid analysis. During these studies, MAH was the recipient of Florey Foundation Fellowships. R.A.D.B. is an NHMRC Senior Research Fellow, and J.D.W. is an NHMRC Principal Research Fellow. Studies at the FNI were supported by the Victorian Government's Operational Infrastructure Support Program.