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

Patil, Nitin A., Hughes, Richard A., Rosengren, K. Johan, Kocan, Martina, Ang, Sheng Yu, Tailhades, Julien, Separovic, Frances, Summers, Roger J., Grosse, Johannes, Wade, John D., Bathgate, Ross A. D. and Hossain, Mohammed Akhter (2016) Engineering of a novel simplified human insulin-Like peptide 5 agonist. Journal of Medicinal Chemistry, 59 5: 2118-2125. doi:10.1021/acs.jmedchem.5b01786

Author Patil, Nitin A.
Hughes, Richard A.
Rosengren, K. Johan
Kocan, Martina
Ang, Sheng Yu
Tailhades, Julien
Separovic, Frances
Summers, Roger J.
Grosse, Johannes
Wade, John D.
Bathgate, Ross A. D.
Hossain, Mohammed Akhter
Title Engineering of a novel simplified human insulin-Like peptide 5 agonist
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2016-03-01
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acs.jmedchem.5b01786
Open Access Status Not Open Access
Volume 59
Issue 5
Start page 2118
End page 2125
Total pages 8
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Formatted 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.
Keyword Chemistry, Medicinal
Pharmacology & Pharmacy
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1023321
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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School of Biomedical Sciences Publications
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