Preparation and Structural, Biochemical, and Pharmaceutical Characterizations of Bile Acid-Modified Long-Acting Exendin-4 Derivatives

Son, Sohee; Chae, Su Young; Kim, Chang-Wan; Choi, Yeong-Won; Jung, Sung Youb; Lee, Seulki; Lee, Kang Choon

doi:10.1021/jm901153x

Cited by 42 publications

(29 citation statements)

References 29 publications

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“…Moreover, the addition of lithocholic acid, a moiety with a similar lipophilic character as estrogen without the metabolic activity of estrogen that has independently been reported to sustain the action profile of exendin-4 (ref. 35), did not enhance GLP-1 pharmacology. Collectively, these results corroborate that estrogen does not enhance the pharmacokinetics of GLP-1.…”

Section: Discussionmentioning

confidence: 87%

Targeted estrogen delivery reverses the metabolic syndrome

Finan

Yang

Ottaway

et al. 2012

Nat Med

255

222

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We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.

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Section: Discussionmentioning

confidence: 87%

Targeted estrogen delivery reverses the metabolic syndrome

Finan

Yang

Ottaway

et al. 2012

Nat Med

255

222

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“…Our data provide a rationale to consider exploring a combinatorial approach. Indeed, examples of bile acid moieties conjugated to a stabilized GLP-1R agonist (modified exenatide peptide) have been reported thus illustrating the chemical possibility of such a therapy [43] . Whether the addition of OCA can enhance the metabolic benefits in patients already on a GLP-1 therapy should be tested.…”

Section: Discussionmentioning

confidence: 99%

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice

Jouihan¹,

Will²,

Guionaud

et al. 2017

Molecular Metabolism

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ObjectiveNonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice.MethodsOCA and IP118 alone and in combination were sub-chronically administered to Lepob/Lepob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lepob/Lepob mice was graded using a customized integrated scoring system.ResultsOCA reduced liver weight and lipid in NASH mice (both by −17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (−21%), liver lipid (−15%), ALT (−29%), and AST (−27%). The combination of OCA + IP118 further reduced liver weight (−29%), liver lipid (−22%), ALT (−39%), and AST (−36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (−4.3% and −3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (−25.3%) to a greater degree than IP118 alone (−12.5%) and further improved glucose tolerance and reduced hepatic lipid.ConclusionOur data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.

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“…However, experiments by Son et al revealed that conjugation of bile acid derivatives to either K12 or K27 still result in a sub-nanomolar affinity of the peptide. In contrast, the conjugation at both positions leads to a loss of affinity of a factor of at least 30, depending on the substrate [[23]]. Jin et al were also able to show that biotinylated exendin-4 derivatives showed no significantly lower affinities compared to unmodified exendin-4 when conjugated at the same positions [[17]].…”

Section: Discussionmentioning

confidence: 99%

A comparison of three 67/68Ga-labelled exendin-4 derivatives for β-cell imaging on the GLP-1 receptor: the influence of the conjugation site of NODAGA as chelator

et al. 2014

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BackgroundVarious diseases derive from pathologically altered β-cells. Their function can be increased, leading to hyperinsulinism, or decreased, resulting in diabetes. Non-invasive imaging of the β-cell-specific glucagon-like peptide receptor-1 (GLP-1R) would allow the assessment of both β-cell mass and derived tumours, potentially improving the diagnosis of various conditions. We tested three new 67/68Ga-labelled derivatives of exendin-4, an agonist of GLP-1R, in vitro and in vivo. We determined the influence of the chelator NODAGA conjugated to resident lysines either at positions 12 and 27 or the C-terminally attached lysine at position 40 on the binding and kinetics of the peptide.MethodsBinding and internalisation of 67Ga-labelled Ex4NOD12, Ex4NOD27 and Ex4NOD40 were tested on Chinese hamster lung (CHL) cells stably transfected to express the GLP-1 receptor (GLP-1R). In vivo biodistribution of 68Ga-labelled peptides was investigated in CD1 nu/nu mice with subcutaneous CHL-GLP-1R positive tumours; the specificity of the binding to GLP-1R was determined by pre-injecting excess peptide.ResultsAll peptides showed good in vitro binding affinities to GLP-1R in the range of 29 to 54 nM. 67/68Ga-Ex4NOD40 and 67/68Ga-Ex4NOD12 show excellent internalisation (>30%) and high specific uptake in GLP-1R positive tissue, but high activity was also found in the kidneys.ConclusionsWe show that of the three peptides, Ga-Ex4NOD40 and Ga-Ex4NOD12 demonstrate the most favourable in vitro properties and in vivo binding to GLP-1R positive tissue. Therefore, we conclude that the lysines at positions 12 and 40 might preferentially be utilised for modifying exendin-4.

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Preparation and Structural, Biochemical, and Pharmaceutical Characterizations of Bile Acid-Modified Long-Acting Exendin-4 Derivatives

Cited by 42 publications

References 29 publications

Targeted estrogen delivery reverses the metabolic syndrome

Targeted estrogen delivery reverses the metabolic syndrome

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice

A comparison of three 67/68Ga-labelled exendin-4 derivatives for β-cell imaging on the GLP-1 receptor: the influence of the conjugation site of NODAGA as chelator

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