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A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity.

By Bianchi, Elisabetta; Carrington, Paul E.; Ingallinella, Paolo; Finotto, Marco; Santoprete, Alessia; Petrov, Aleksandr; Eiermann, George; Kosinski, Jennifer; Marsh, Donald J.; Pocai, Alessandro; et al
From Bioorganic & Medicinal Chemistry (2013), 21(22), 7064-7073. Language: English, Database: CAPLUS, DOI:10.1016/j.bmc.2013.09.016

Peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) are rapidly gaining favor as antidiabetic agents, since in addn. to increasing glucose-dependent insulin secretion, they also cause wt. loss. Oxyntomodulin (OXM), a natural peptide with sequence homol. to both glucagon and GLP-1, has glucose-lowering activity in rodents and anorectic activity in rodents and humans, but its clin. utility is limited by a short circulatory half-life due to rapid renal clearance and degrdn. by dipeptidyl peptidase IV (DPP-IV). Here, the authors describe the development of a novel DPP-IV-resistant, long-acting GLP1R agonist, based on derivatization of a suitably chosen OXM analog with high mol. wt. polyethylene glycol (PEG) (‘PEGylation’). PEG-OXM exerts an anti-hyperglycemic effect in diet-induced obese (DIO) mice in a glucose-dependent manner, with a maximally efficacious dose of 0.1 mg/kg, and reduces food intake and body wt. with a minimally efficacious dose of 1 mg/kg. If this pharmacol. is recapitulated in patients with type 2 diabetes, these results indicate PEG-OXM as a potential novel once-weekly GLP-1 mimetic with both glucose-lowering activity and wt. loss efficacy.

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