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

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)2118-2125
Number of pages8
JournalJournal of Medicinal Chemistry
Volume59
Issue number5
DOIs
Publication statusPublished - 10 Mar 2016

Cite this

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 ; Bathgate, Ross A D ; Hossain, Mohammed Akhter. / Engineering of a novel simplified human insulin-like peptide 5 agonist. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 5. pp. 2118-2125.
@article{179d2cf47a0447af8e35b4594e7665bc,
title = "Engineering of a novel simplified human insulin-like peptide 5 agonist",
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.",
author = "Patil, {Nitin A.} and Hughes, {Richard A.} and Rosengren, {K. Johan} and Martina Kocan and Ang, {Sheng Yu} and Julien Tailhades and Frances Separovic and Summers, {Roger J.} and Johannes Grosse and John Wade and Bathgate, {Ross A D} and Hossain, {Mohammed Akhter}",
year = "2016",
month = "3",
day = "10",
doi = "10.1021/acs.jmedchem.5b01786",
language = "English",
volume = "59",
pages = "2118--2125",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "5",

}

Patil, NA, Hughes, RA, Rosengren, KJ, Kocan, M, Ang, SY, Tailhades, J, Separovic, F, Summers, RJ, Grosse, J, Wade, J, Bathgate, RAD & Hossain, MA 2016, 'Engineering of a novel simplified human insulin-like peptide 5 agonist' Journal of Medicinal Chemistry, vol. 59, no. 5, pp. 2118-2125. https://doi.org/10.1021/acs.jmedchem.5b01786

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; Bathgate, Ross A D; Hossain, Mohammed Akhter.

In: Journal of Medicinal Chemistry, Vol. 59, No. 5, 10.03.2016, p. 2118-2125.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Engineering of a novel simplified human insulin-like peptide 5 agonist

AU - Patil, Nitin A.

AU - Hughes, Richard A.

AU - Rosengren, K. Johan

AU - Kocan, Martina

AU - Ang, Sheng Yu

AU - Tailhades, Julien

AU - Separovic, Frances

AU - Summers, Roger J.

AU - Grosse, Johannes

AU - Wade, John

AU - Bathgate, Ross A D

AU - Hossain, Mohammed Akhter

PY - 2016/3/10

Y1 - 2016/3/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84969255732&partnerID=8YFLogxK

UR - http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01786

U2 - 10.1021/acs.jmedchem.5b01786

DO - 10.1021/acs.jmedchem.5b01786

M3 - Article

VL - 59

SP - 2118

EP - 2125

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -