Contribution of site-specific PEGylation to the dipeptidyl peptidase IV stability of glucose-dependent insulinotropic polypeptide

Salhanick, Arthur I.; Clairmont, Kevin B.; Buckholz, Thomas M.; Pellegrino, Carla M.; Ha, Sha; Lumb, Kevin J.

doi:10.1016/j.bmcl.2005.06.002

Cited by 29 publications

(22 citation statements)

References 23 publications

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“…Proteolytic sensitivity is a significant determinant to the biological half‐life of peptides. As such, a number of modification strategies have been investigated in efforts to render peptides ineffective substrates for proteolytic enzymes .…”

Section: Introductionmentioning

confidence: 99%

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Krasniqi

Scruten

Piller

et al. 2012

Journal of Peptide Science

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Peptide modifications that improve pharmacological properties are of considerable therapeutic importance. Here we consider the retro (R), inversed (D) and retro-inversed (RI) isomers of glucagon with respect to structure, stability, toxicity and biological activity. Biologically, RI-glucagon demonstrated comparable in vivo activity as L-glucagon with respect to magnitude and duration of blood sugar elevation following i.p. administration to mice. Structurally, the isomers were investigated through circular dichroism (CD) and nanopore analysis. CD demonstrated a conserved potential for formation of secondary structure, which was independent of the direction of the peptide (L vs R; D vs RI) as well as formation of symmetry-related structures for the chiral isomers (L vs D; R vs RI). CD, therefore, discriminated chiral but not directional isomers. Nanopore analysis, which depends on interaction of the peptides with chiral pores, discriminated all four isomers on the basis of unique signatures of bumping and translocation. Nanopore analysis offered greater opportunity than CD to discriminate the isomers although neither technique provided a definitive biomarker of biological activity. Functionally, the R and RI isomers resist proteolytic degradation and none of the isomers possess hemolytic activity or cellular toxicity. Collectively, this investigation highlights the potentials and limitations of CD and nanopore analysis for investigation of peptide isomers as well as offering insight into the structural criteria to mimic peptide biological activity. For this example, retro-inversion, through undefined contributions of increased stability and maintained biological activity, was best suited to mimic the biological activity of the parent peptide.

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Section: Introductionmentioning

confidence: 99%

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Krasniqi

Scruten

Piller

et al. 2012

Journal of Peptide Science

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“…[12][13][14] PEGylation-covalent modification with polyethylene glycol (PEG) -is viewed as a practical way of improving the therapeutic values of antidiabetic peptides/proteins. [15][16][17][18][19] It has been well documented that this biotechnique increases metabolic resistance 20 and decreases renal clearance/tissue affinity. 21 Moreover, PEGylated peptides can modulate their in vivo pharmacokinetic profiles by simply changing the Mw of the pendant PEG, and thus increased PEG Mw enhances the aforementioned in vivo properties.…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17][18][19] This PEGylated GLP-1 analog displayed a preserved biological activity as well as profoundly improved metabolic stabilities against DPP-IV and NEP 24.11. Moreover, a pharmacokinetic evaluation in rats demonstrated the extended plasma half-life and lower systemic clearance of this analog.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers

Chae

Chun

Lee

et al. 2009

Journal of Pharmaceutical Sciences

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“…PEGylation of peptides and proteins has been shown to prolong circulating half‐lives through decreased renal clearance and increased proteolytic stability ( Harris and Chess, 2003 ). The usefulness of this approach has been successfully exploited using glucagon‐like peptide‐1 (GLP‐1) and positive effects on stability and bioactivity have been obtained with a truncated form of GIP ( Salhanick et al ., 2005 ; Lee et al ., 2006 ).…”

Section: Introductionmentioning

confidence: 99%

(Pro³)GIP[mPEG]: novel, long‐acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity‐diabetes (diabesity) therapy

McClean

Irwin

Hunter

et al. 2008

British J Pharmacology

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Background and purpose: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro 3 )GIP) can reverse or prevent many of the metabolic abnormalities associated with dietinduced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro 3 )GIP, (Pro 3 )GIP mini-polyethylene glycol ((Pro 3 )GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. Experimental approach: We studied the actions of (Pro 3 )GIP [mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity.

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Contribution of site-specific PEGylation to the dipeptidyl peptidase IV stability of glucose-dependent insulinotropic polypeptide

Cited by 29 publications

References 23 publications

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers

(Pro³)GIP[mPEG]: novel, long‐acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity‐diabetes (diabesity) therapy

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Contribution of site-specific PEGylation to the dipeptidyl peptidase IV stability of glucose-dependent insulinotropic polypeptide

Cited by 29 publications

References 23 publications

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers

(Pro3)GIP[mPEG]: novel, long‐acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity‐diabetes (diabesity) therapy

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Product

Resources

About

(Pro³)GIP[mPEG]: novel, long‐acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity‐diabetes (diabesity) therapy