N-terminally modified glucagon-like peptide-1(7â36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

O’Harte, Finbarr

doi:10.1016/s0304-4165(99)00214-7

Cited by 46 publications

(36 citation statements)

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“…This raises the possibility that glycosylation may function either as a signal for cleavage or as a means of preventing amino-terminal degradation of the protein following cleavage from its acylated anchor. In support of this latter idea, amino-terminal glycosylation of the cholecystokinin octapeptide (CCK-8) and of glucagon-like peptide-1-(7-36) amide (Tglp-1) leads to their increased resistance to serum aminopeptidase degradation (36,37). In their study of the M. tuberculosis 19-kDa antigen, Herrmann and colleagues (17) also described a truncated form of the protein in which the glycosylation motif formed the new NH 2 terminus.…”

Section: Discussionmentioning

confidence: 99%

The MPB83 Antigen from Mycobacterium bovis ContainsO-Linked Mannose and (1 → 3)-Mannobiose Moieties

Michell

Whelan

Wheeler

et al. 2003

Journal of Biological Chemistry

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Mycobacterium tuberculosis and Mycobacterium bovis, the causative agents of human and bovine tuberculosis, have been reported to express a range of surface and secreted glycoproteins, although only one of these has been subjected to detailed structural analysis. We describe the use of a genetic system, in conjunction with lectin binding, to characterize the points of attachment of carbohydrate moieties to the polypeptide backbone of a second mycobacterial glycoprotein, antigen MPB83 from M. bovis. Biochemical and structural analysis of the native MPB83 protein and derived peptides demonstrated the presence of 3 mannose units attached to two threonine residues. Mannose residues were joined by a (1 3 3) linkage, in contrast to the (1 3 2) linkage previously observed in antigen MPT32 from M. tuberculosis and the (1 3 2) and (1 3 6) linkages in other mycobacterial glycolipids and polysaccharides. The identification of glycosylated antigens within the M. tuberculosis complex raises the possibility that the carbohydrate moiety of these glycoproteins might be involved in pathogenesis, either by interaction with mannose receptors on host cells, or as targets or modulators of the cell-mediated immune response. Given such a possibility characterization of mycobacterial glycoproteins is a step toward understanding their functional role and elucidating the mechanisms of mycobacterial glycosylation.Protein glycosylation is ubiquitous in eukaryotes and the diverse array of carbohydrate moieties that can be fashioned to a polypeptide backbone makes glycoproteins ideal molecules to allow specific interactions with other molecules. In contrast, the number of reports of this post-translational modification by prokaryotes is comparatively low. Examples of eubacterial glycoproteins identified to date include cell surface or secreted proteins of pathogens that have antigenic properties and play a role in host pathogen interaction (1-6). Glycosylation of pilin has been postulated to enhance the adherence of Neisseria meningitidis to endothelial cells (2), whereas N-glycosylation of the platelet aggregation-associated protein of Staphylococcus sanguis may promote colonization of the endocardium (7, 8).Removal of a sero-specific glycosyl moiety from the flagellin of Campylobacter jejuni has been reported to alter the O antigenicity of the organism (9, 10). Similarly, Romain et al. (11) demonstrated that removal of covalently bound mannose from the Mycobacterium tuberculosis antigen MPT32 reduced by 10-fold its ability to elicit a delayed-type hypersensitivity reaction in guinea pigs immunized with Mycobacterium bovis BCG.M. tuberculosis and M. bovis are closely related members of the "M. tuberculosis complex" (MTb complex) that secrete a series of immunodominant antigens that have been reported to be glycosylated, on the basis of their ability to bind lectins such as concanavalin A (ConA) 1 (12-15). Structural confirmation of protein glycosylation by mycobacteria was provided by detailed chemical compositional analysis of MPT32, a 45...

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Section: Discussionmentioning

confidence: 99%

The MPB83 Antigen from Mycobacterium bovis ContainsO-Linked Mannose and (1 → 3)-Mannobiose Moieties

Michell

Whelan

Wheeler

et al. 2003

Journal of Biological Chemistry

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“…Modifications introduced at the NH 2 -terminus histidine residue have also been studied. 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].…”

Section: H Glp-1 Synthetic Analogs Obtained By Chemical Modificationmentioning

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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“…Exendin-4 in vivo seems considerably more potent than GLP-1 (14,28,39,46) and may have potential as a therapeutic agent for use in type 2 diabetes. A number of GLP-1 analogs have been tested in vitro and in vivo in both rats and mice (2,20,29,34). They also appear to have greater plasma stability and a longer action than GLP-1, indicating a number of potential therapeutic agents acting at the GLP-1 receptor.…”

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confidence: 99%

Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers

Edwards

Stanley

Davis

et al. 2001

American Journal of Physiology-Endocrinology and Metabolism

437

294

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Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 281: E155-E161, 2001.-Exendin-4 is a long-acting potent agonist of the glucagon-like peptide 1 (GLP-1) receptor and may be useful in the treatment of type 2 diabetes and obesity. We examined the effects of an intravenous infusion of exendin-4 (0.05 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) compared with a control saline infusion in healthy volunteers. Exendin-4 reduced fasting plasma glucose levels and reduced the peak change of postprandial glucose from baseline (exendin-4, 1.5 Ϯ 0.3 vs. saline, 2.2 Ϯ 0.3 mmol/l, P Ͻ 0.05). Gastric emptying was delayed, as measured by the paracetamol absorption method. Volunteers consumed 19% fewer calories at a free-choice buffet lunch with exendin-4 (exendin-4, 867 Ϯ 79 vs. saline 1,075 Ϯ 93 kcal, P ϭ 0.012), without reported side effects. Thus our results are in accord with the possibility that exendin-4 may be a potential treatment for type 2 diabetes, particularly for obese patients, because it acts to reduce plasma glucose at least partly by a delay in gastric emptying, as well as by reducing calorie intake.glucagon-like peptide 1; glycemia; gastric emptying; type 2 diabetes GLUCAGON-LIKE PEPTIDE 1 (GLP-1) is released from the intestine in response to nutrient ingestion (20). Exogenous administration to humans has a number of effects that result in a decrease in plasma glucose levels. It stimulates plasma insulin levels (20), suppresses glucagon levels (22), and delays gastric emptying (27,45). There is some evidence that GLP-1 may also increase peripheral insulin sensitivity (4, 16), although this is controversial (30). GLP-1 has been shown to decrease food intake and body weight in rats when administered into the third cerebral ventricle (24,42). A number of groups have looked at the effect of GLP-1 on satiety and food intake in humans, and it appears to parallel the effect seen in rats, although not always (11,18,23,25). Recently, we infused the GLP-1 antagonist, exendin-(9-39), in humans and demonstrated that endogenous GLP-1 regulates plasma glucose levels (10), and its effects on plasma glucagon and gastric emptying appear to be physiological (10). GLP-1 has also been shown to have a physiological role in glucose homeostasis in the rat (21, 44), mouse (38), and baboon (5), although it appears that this is not always the case, as exogenous administration has little effect in the calf (9).Exendin-4 is a 39-amino acid peptide isolated from the Gila monster salivary gland and acts as an agonist of the GLP-1 receptor (13, 40). Exendin-4 appears to have a considerably greater biological half-life than GLP-1 (14, 39, 46). We (10) have shown that the circulating half-life of the truncated exendin-4, exendin-(9-39), is 33 Ϯ 4 min in humans; this compares with a half-life for the biologically active intact GLP-1 of 1-3 min in a number of species (6,19,32). Thus it would appear likely that exendin-4 has a longer circulating and biological half-life than GLP-1 in hu...

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N-terminally modified glucagon-like peptide-1(7â36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

Cited by 46 publications

References 47 publications

The MPB83 Antigen from Mycobacterium bovis ContainsO-Linked Mannose and (1 → 3)-Mannobiose Moieties

The MPB83 Antigen from Mycobacterium bovis ContainsO-Linked Mannose and (1 → 3)-Mannobiose Moieties

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

Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers

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N-terminally modified glucagon-like peptide-1(7â36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

Cited by 46 publications

References 47 publications

The MPB83 Antigen from Mycobacterium bovis ContainsO-Linked Mannose and (1 → 3)-Mannobiose Moieties

The MPB83 Antigen from Mycobacterium bovis ContainsO-Linked Mannose and (1 → 3)-Mannobiose Moieties

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

Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers

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N-terminally modified glucagon-like peptide-1(7â36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo