1区 · 生物学
Article
作者: Jan, Christelle ; Konkar, Anish ; Eriksson, Olof ; Prochnow, Hans-Peter ; Evers, Andreas ; Moessinger, Christine ; Kissner, Thomas ; Lorenz, Katrin ; Elvert, Ralf ; Bossart, Martin ; Agueusop, Inoncent ; Hübschle, Thomas ; Wagner, Michael ; Johansson, Lars ; Porksen, Niels ; Nitsche, Almut ; Nowotny, Irene ; Einig, Christine ; Dietert, Gabriele ; Kloeckener, Tim ; Pierrou, Stefan ; Dietz-Baum, Yasmin ; Gassenhuber, Johann ; Smith, William B ; Rharbaoui, Faiza ; Velikyan, Irina
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.