GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro

Gallwitz, Baptist; Ropeter, Torsten; Morys-Wortmann, Corinna; Mentlein, Rolf; Siegel, Erhard; Schmidt, Wolfgang E.

doi:10.1016/s0167-0115(99)00095-6

Cited by 66 publications

(52 citation statements)

References 33 publications

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“…Overall, these data concur with previous findings that N-terminal extension of GLP-1 at His 7 prevents DPP IV action, providing a simple means of generating stable long-acting GLP-1 analogues (Gallwitz et al 2000, O'Harte et al 2000. The results support previous observations that such modifications to GLP-1 may result in some compromise of in vitro receptor binding affinity and cAMP production (Gallwitz et al 2000).…”

Section: Discussionsupporting

confidence: 91%

“…The results support previous observations that such modifications to GLP-1 may result in some compromise of in vitro receptor binding affinity and cAMP production (Gallwitz et al 2000). However, it is clear that these limitations do not necessarily compromise improved antihyperglycaemic potential in vivo due to prolonged circulating half-life and enhanced effects of some analogues on other target sites in addition to the stimulation of insulin secretion.…”

Section: Discussionsupporting

confidence: 88%

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N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Green¹,

Mooney²,

Gault³

et al. 2004

Journal of Endocrinology

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Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His 7 -modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC 50 values 32·9 and 6·7 nM, respectively) compared with native GLP-1 (IC 50 0·37 nM). Similarly, both analogues stimulated cAMP production with EC 50 values of 16·3 and 27 nM respectively compared with GLP-1 (EC 50 4·7 nM). However, N-acetyl-GLP-1 and Npyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5·6 mM glucose (P,0·05 to P,0·001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Green¹,

Mooney²,

Gault³

et al. 2004

Journal of Endocrinology

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“…Native mammalian GLP-1 is very sensitive to degradation by proteases (Goke et al, 1993;Thorens et al, 1993;Mentlei, 1999;Yamamoto et al, 2002Yamamoto et al, , 2003; for this reason, we additionally evaluated the effect of the protease-resistant long-acting GLP-1 receptor agonist Exn4 Goke et al, 1993;Gallwitz et al, 2000) on the frequency of action potentials in hypocretin neurons. Exn4 (1 M) induced a robust depolarization of the membrane potential and increased the firing rate of hypocretin neurons (Fig.…”

Section: Glucagon-like Peptide 1 Excites Hypocretin Neuronsmentioning

confidence: 99%

Glucagon-Like Peptide 1 Excites Hypocretin/Orexin Neurons by Direct and Indirect Mechanisms: Implications for Viscera-Mediated Arousal

Acuña-Goycolea¹,

Pol²

2004

J. Neurosci.

112

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“…For example, NH 2 -terminal glycation to generate His(7)-glucitol-GLP-1 was shown to generate a peptide that exhibited DPP IV resistance, insulin secretagogue activity, and which lowered concentrations of blood glucose in rats [136]. Additional NH 2 -terminus modifications that have been studied include Nmethylation, α-methylation, des amidation, and imidazole lactic acid substitution [137]. These compounds retain their ability to bind to the GLP-1 receptor, and are also reported to stimulate cAMP production in an insulinoma cell line, thereby suggesting a possible in vivo insulinotropic activity that has yet to be fully evaluated.…”

mentioning

confidence: 99%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

123

105

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Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing b-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate b-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted. Keywords GLP-1; diabetes mellitus; insulin secretion A. INTRODUCTIONGlucagon-like peptide-1-(7-36)-amide (GLP-1, also known as t-GLP-1 or GLIP) is an intestinally-derived insulinotropic hormone that has attracted considerable attention by virtue of its proven ability to act as a blood glucose lowering agent. The efficacy with which GLP-1 lowers concentrations of blood glucose in type 2 diabetic subjects (adult onset diabetes mellitus) has prompted clinical investigations whereby the therapeutic value of GLP-1 as an antidiabetogenic agent has been substantiated. Earlier studies revealed that © 2003 Bentham Science Publishers Ltd. * Address correspondence to this author at the Department of Physiology and Neuroscience, MSB 442, New York University School of Medicine, 550 First Avenue, NY 10016, New York, USA; Tel: 212-263-5434; Fax: 212-689-9060; holzg01@popmail.med.nyu.edu. NIH Public Access Author ManuscriptCurr Med Chem. Author manuscript; available in PMC 2010 July 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGLP-1 is an ...

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GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro

Cited by 66 publications

References 33 publications

N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Glucagon-Like Peptide 1 Excites Hypocretin/Orexin Neurons by Direct and Indirect Mechanisms: Implications for Viscera-Mediated Arousal

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

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