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

Journal of Medicinal Chemistry
Nitin A PatilMohammed A Hossain

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 (K(A15)) 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.

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Citations

Dec 7, 2016·British Journal of Pharmacology·Nitin A PatilMohammed Akhter Hossain
May 4, 2017·Journal of Peptide Science : an Official Publication of the European Peptide Society·Kishore ThalluriRichard D DiMarchi
Mar 10, 2017·Archives of Biochemistry and Biophysics·Meng-Jun HuZhan-Yun Guo
Feb 22, 2018·ChemMedChem·Alexander N ZaykovRichard D DiMarchi
Nov 30, 2019·Scientific Reports·Praveen PraveenMohammed Akhter Hossain
Nov 27, 2016·Naunyn-Schmiedeberg's Archives of Pharmacology·Sheng Y AngRoger J Summers
Sep 29, 2018·Pharmacology Research & Perspectives·Adam L ValkovicRoss A D Bathgate
Jan 29, 2020·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Shanti DiwakarlaJohn B Furness
Mar 30, 2019·Chemistry : a European Journal·Nitin A PatilJulien Tailhades
Dec 19, 2020·ACS Medicinal Chemistry Letters·Xiaozhou ZhangMohammed Akhter Hossain
Jun 7, 2018·Organic Letters·Alexander N ZaykovRichard D DiMarchi
Oct 19, 2021·ACS Pharmacology & Translational Science·Ruslan V PustovitMohammed Akhter Hossain

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