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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24 Citations (Scopus)


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

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