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 |
|---|---|
| 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 |
Cite this
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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 journal › Article › Research › peer-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 -