Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues modified at the N-terminus

AM Lynch, P Patahk, YE Flatt, Victor Gault, Finbarr O'Harte, Nigel Irwin, Peter Flatt

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Abstract

Oxyntomodulin (Oxm) possesses beneficial biological actions for the potential treatment of obesity-diabetes. However, rapid inactivation by dipeptidyl peptidase-4 (DPP-4) results in a short half-life, hindering therapeutic applicability. In the present study, six Oxm analogues namely, (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were synthesised and tested for DPP-4 stability and biological activity. Native Oxm, (Thr2)Oxm and (Asp3)Oxm were rapidly degraded by DPP-4, while (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were resistant to degradation. All peptides stimulated cAMP production (P
LanguageEnglish
Pages69-78
JournalEuropean Journal of Pharmacology
Volume743
DOIs
Publication statusPublished - 22 Sep 2014

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Oxyntomodulin
Appetite
Glucose
Dipeptidyl Peptidase 4

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title = "Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues modified at the N-terminus",
abstract = "Oxyntomodulin (Oxm) possesses beneficial biological actions for the potential treatment of obesity-diabetes. However, rapid inactivation by dipeptidyl peptidase-4 (DPP-4) results in a short half-life, hindering therapeutic applicability. In the present study, six Oxm analogues namely, (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were synthesised and tested for DPP-4 stability and biological activity. Native Oxm, (Thr2)Oxm and (Asp3)Oxm were rapidly degraded by DPP-4, while (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were resistant to degradation. All peptides stimulated cAMP production (P",
author = "AM Lynch and P Patahk and YE Flatt and Victor Gault and Finbarr O'Harte and Nigel Irwin and Peter Flatt",
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TY - JOUR

T1 - Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues modified at the N-terminus

AU - Lynch, AM

AU - Patahk, P

AU - Flatt, YE

AU - Gault, Victor

AU - O'Harte, Finbarr

AU - Irwin, Nigel

AU - Flatt, Peter

PY - 2014/9/22

Y1 - 2014/9/22

N2 - Oxyntomodulin (Oxm) possesses beneficial biological actions for the potential treatment of obesity-diabetes. However, rapid inactivation by dipeptidyl peptidase-4 (DPP-4) results in a short half-life, hindering therapeutic applicability. In the present study, six Oxm analogues namely, (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were synthesised and tested for DPP-4 stability and biological activity. Native Oxm, (Thr2)Oxm and (Asp3)Oxm were rapidly degraded by DPP-4, while (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were resistant to degradation. All peptides stimulated cAMP production (P

AB - Oxyntomodulin (Oxm) possesses beneficial biological actions for the potential treatment of obesity-diabetes. However, rapid inactivation by dipeptidyl peptidase-4 (DPP-4) results in a short half-life, hindering therapeutic applicability. In the present study, six Oxm analogues namely, (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were synthesised and tested for DPP-4 stability and biological activity. Native Oxm, (Thr2)Oxm and (Asp3)Oxm were rapidly degraded by DPP-4, while (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were resistant to degradation. All peptides stimulated cAMP production (P

U2 - 10.1016/j.ejphar.2014.09.018

DO - 10.1016/j.ejphar.2014.09.018

M3 - Article

VL - 743

SP - 69

EP - 78

JO - European Journal of Pharmacology

T2 - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -