Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist

Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide ago...

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Veröffentlicht in:New journal of chemistry 2021-11, p.59
Hauptverfasser: Bossart, Martin, Wagner, Michael, Elvert, Ralf, Evers, Andreas, Hu, Thomas, Kloeckener, Tim, Lorenz, Katrin, Moessinger, Christine, Eriksson, Olof, Velikyan, Irina, Pierrou, Stefan, Johansson, Lars, Dietert, Gabriele, Dietz-Baum, Yasmin, Kissner, Thomas, Nowotny, Irene, Einig, Christine, Jan, Christelle, Rharbaoui, Faiza, Gassenhuber, Johann, Prochnow, Hans-Peter, Agueusop, Inoncent, Porksen, Niels, Smith, William B., Nitsche, Almut, Konkar, Anish
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container_start_page 59
container_title New journal of chemistry
container_volume
creator Bossart, Martin
Wagner, Michael
Elvert, Ralf
Evers, Andreas
Hu, Thomas
Kloeckener, Tim
Lorenz, Katrin
Moessinger, Christine
Eriksson, Olof
Velikyan, Irina
Pierrou, Stefan
Johansson, Lars
Dietert, Gabriele
Dietz-Baum, Yasmin
Kissner, Thomas
Nowotny, Irene
Einig, Christine
Jan, Christelle
Rharbaoui, Faiza
Gassenhuber, Johann
Prochnow, Hans-Peter
Agueusop, Inoncent
Porksen, Niels
Smith, William B.
Nitsche, Almut
Konkar, Anish
description Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
doi_str_mv 10.1016/j.cmet.2021.12.005
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subjects Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Science & Technology
title Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
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