Projects per year
Abstract
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 language | English |
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Pages (from-to) | 2118-2125 |
Number of pages | 8 |
Journal | Journal of Medicinal Chemistry |
Volume | 59 |
Issue number | 5 |
DOIs | |
Publication status | Published - 10 Mar 2016 |
Projects
- 1 Finished
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The Janus face of G Protein-Coupled Receptors: Implications for Disease Mechanisms and Opportunities for Drug Discovery
Sexton, P. (Primary Chief Investigator (PCI)), Bunnett, N. (Chief Investigator (CI)), Christopoulos, A. (Chief Investigator (CI)) & Summers, R. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/14 → 31/12/18
Project: Research