The Positive Charge of the Imidazole Side Chain of Histidine7 Is Crucial for GLP-1 Action.

Hareter, Alexandra; Hoffmann, Eike; Bode, Hans-Peter; Göke, Burkhard; Göke, Rüdiger

doi:10.1507/endocrj.44.701

Cited by 36 publications

(34 citation statements)

References 11 publications

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“…Unfortunately, the N-terminal selective chemical pegylation of GLP-1 peptides results in a monoconjugated derivative with negligible in vivo activity due to the fact that the N-terminal histidine residue is crucial for effective receptor recognition and maintenance of biological action [18,19]. …”

Section: Discussionmentioning

confidence: 99%

Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes

Selis¹,

Schrepfer

Sanna³

et al. 2012

Results in Pharma Sciences

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Human glucagon-like peptide-1 (GLP-1) is a physiological gastrointestinal peptide with glucose-dependent insulinotropic effects which is therefore considered an interesting antidiabetic agent. However, after in vivo administration, exogenous GLP-1 does not exert its physiological action due to the combination of rapid proteolytic degradation by ubiquitous dipeptidyldipeptidase IV (DPP IV) enzyme and renal clearance resulting in an extremely short circulating half-life. In this work we describe the conjugation of GLP-1-(7-36)-amide derivatives with polyethylene glycol (PEG) by enzymatic site-specific transglutamination reaction as an approach to reduce both the proteolysis and the renal clearance rates.The compound GLP-1-(7-36)-amide-Q23-PEG 20 kDa monopegylated on the single glutamine residue naturally present in position 23 maintained the ability to activate the GLP-1 receptor expressed in the rat β-cell line RIN-m5F with nanomolar potency along with an increased in vitro resistance to DDP IV and a circulating half-life of about 12 h after subcutaneous administration in rats. These properties enabled GLP-(7-36)-amide-Q23-PEG 20 kDa to exert a glucose-stabilizing effect for a period as long as 8 h, as demonstrated by a single subcutaneous injection to diabetic mice concomitantly challenged with an oral glucose load.The results reported in this work indicate that GLP-(7-36)-amide-Q23-PEG 20 kDa could be a lead compound for the development of long-lasting anti-diabetic agents useful in the treatment of type 2 diabetes affected patients.

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Section: Discussionmentioning

confidence: 99%

Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes

Selis¹,

Schrepfer

Sanna³

et al. 2012

Results in Pharma Sciences

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“…Other amino acids in the N-terminus at positions 10 (glycine), 12 (phenylalanine), 13 (threonine), 15 (aspartate), and at positions 28 and 29 in the C-terminus are also directly involved in the receptor interaction. [121314] Alteration of these sites should theoretically lead to modification of GLP-1 resistant to DPP-4 inhibition, thereby prolonging its half-life and efficiency.…”

Section: Glucagon-like Peptide-1 Systemmentioning

confidence: 99%

Glucagon-like peptide-1 analogues: An overview

Gupta

2013

Indian J Endocr Metab

136

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Abnormalities of the incretin axis have been implicated in the pathogenesis of type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1) and gastroinhibitory intestinal peptide constitutes >90% of all the incretin function. Augmentation of GLP-1 results in improvement of beta cell health in a glucose-dependant manner (post-prandial hyperglycemia) and suppression of glucagon (fasting hyperglycemia), amongst other beneficial pleiotropic effects. Native GLP-1 has a very short plasma half-life and novel methods have been developed to augment its half life, such that its anti-hyperglycemic effects can be exploited. They can be broadly classified as exendin-based therapies (exenatide, exenatide once weekly), DPP-4-resistant analogues (lixisenatide, albiglutide), and analogues of human GLP-1 (liraglutide, taspoglutide). Currently, commercially available analogues are exenatide, exenatide once weekly, and liraglutide. This review aims to provide an overview of most GLP-1 analogues.

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“…Structure-activity studies in mammalian cells identified His 7 , Phe 12 , Phe 28 , and Ile 29 as being essential for function [86,87,88]. Hareter et al [87] reported that modification or substitution of His 7 resulted in an almost complete loss of biological activity and that this residue could possibly attracted to the negatively charged carboxylic group of Asp 15 as suggested in glucagon.…”

Section: Glp-1mentioning

confidence: 99%

“…Hareter et al [87] reported that modification or substitution of His 7 resulted in an almost complete loss of biological activity and that this residue could possibly attracted to the negatively charged carboxylic group of Asp 15 as suggested in glucagon. Adelhorst et al [88], additionally, demonstrated that side chains in positions 7, 10, 12, 13, and 15 are engaged in the receptor interaction, while residues at positions 28 and 29 are important for GLP-1 to adopt the architecture recognized by the receptor.…”

Section: Glp-1mentioning

confidence: 99%

The Secretin/Pituitary Adenylate Cyclase-Activating Polypeptide/ Vasoactive Intestinal Polypeptide Superfamily in the Central Nervous System

Chu¹,

Lee²,

Siu³

et al. 2006

CNSAMC

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The secretin/PACAP/VIP superfamily contains at least ten brain-gut peptides, including secretin, pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), glucagon, glucagon-like peptide-1 (GLP-1), glucagon like peptide-2 (GLP-2), gastric inhibitory polypeptide (GIP), peptide histidine isoleucine (PHI) or peptide histidine methionine (PHM), and growth hormone-releasing hormone (GHRH). These peptides exhibit a wide tissue distribution in the peripheral systems, indicating their pleiotrophic actions in the body. Meanwhile, their functions in the central nervious system (CNS) have also been consolidated recently. For instance, most of these peptides have shown to serve as neurotransmitters, neuromodulators, neurotrophic factors, and/or neurohormones in the brain, and hence, their potential as novel CNS agents in treating neurological disorders including Autism, Alzheimer's disease, Parkinson's disease and HIV-associated neuronal cell death were recently exploited. In this article, recent progress in research of peptides in this family with particular emphasis on structures, their central functions and potential use in the treatment of neuronal diseases are reviewed.

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The Positive Charge of the Imidazole Side Chain of Histidine7 Is Crucial for GLP-1 Action.

Abstract: Abstract.Glucagon-like peptide-1(7-36)amide/(7-37)

Cited by 36 publications

References 11 publications

Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes

Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes

Glucagon-like peptide-1 analogues: An overview

The Secretin/Pituitary Adenylate Cyclase-Activating Polypeptide/ Vasoactive Intestinal Polypeptide Superfamily in the Central Nervous System

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