Abstract
Incretin-based peptides are effective therapeutics for treating type 2 diabetes mellitus (T2DM). Oxyntomodulin (OXM), a dual agonist of GLP-1R and GCGR, has shown superior weight loss and glucose lowering effects, compared to single GLP-1R agonists. To overcome the short half-life and rapid renal clearance of OXM, which limit its therapeutic potential, both lipid and PEG modified OXM analogs have been reported. However, these approaches often result in reduced potency or PEG-associated toxicity. Herein, we report a new class of cross-linked OXM analogs that show increased plasma stability and higher potency in activating both GLP-1R and GCGR. Moreover, the extended in vivo half-life results in superior antihyperglycemic activity in mice compared to the wild-type OXM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cross-Linking Reagents / chemistry
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Cross-Linking Reagents / pharmacokinetics
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Cross-Linking Reagents / pharmacology
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Glucagon-Like Peptide-1 Receptor / agonists*
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Glucagon-Like Peptide-1 Receptor / metabolism
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HEK293 Cells
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Humans
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Hypoglycemic Agents / blood
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacology*
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Mice
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Models, Molecular
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Molecular Sequence Data
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Oxyntomodulin / blood
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Oxyntomodulin / chemistry*
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Oxyntomodulin / pharmacology*
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Proteolysis
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Receptors, Glucagon / agonists*
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Receptors, Glucagon / metabolism
Substances
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Cross-Linking Reagents
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents
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Oxyntomodulin
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Receptors, Glucagon