Engineering of a novel simplified human insulin-like peptide 5 agonist

Nitin A. Patil, Richard A. Hughes, K. Johan Rosengren, Martina Kocan, Sheng Yu Ang, Julien Tailhades, Frances Separovic, Roger J. Summers, Johannes Grosse, John Wade, Ross A D Bathgate, Mohammed Akhter Hossain

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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 nM). The SAR study also identified a key residue (KA15) in the A-chain of mINSL5 that contributes to improved RXFP4 affinity and potency of mINSL5 compared with hINSL5. This knowledge ultimately led us to engineer a minimized hINSL5 mimetic agonist that retains native hINSL5-like RXFP4 affinity and potency at human RXFP4. This minimized analogue was synthesized in 17.5-fold higher yield and in less time compared with hINSL5.

Original languageEnglish
Pages (from-to)2118-2125
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - 10 Mar 2016

Cite this

Patil, N. A., Hughes, R. A., Rosengren, K. J., Kocan, M., Ang, S. Y., Tailhades, J., Separovic, F., Summers, R. J., Grosse, J., Wade, J., Bathgate, R. A. D., & Hossain, M. A. (2016). Engineering of a novel simplified human insulin-like peptide 5 agonist. Journal of Medicinal Chemistry, 59(5), 2118-2125.