Nature: Unimolecular GLP-1R/GIPR/PPARα/γ/δ Quintuple Agonist Conjugate Reverses Obesity and Insulin Resistance in Mice
A Nature paper from Liskiewicz, DiMarchi, Tschöp, Müller and colleagues introduces a unimolecular peptide-drug conjugate that combines a GLP-1R/GIPR co-agonist peptide with the pan-PPAR (α/γ/δ) agonist lanifibranor via a pH-sensitive linker. After receptor-mediated internalization, the linker cleaves and lanifibranor escapes to the nucleus to activate PPARs while the peptide moiety drives GLP-1R/GIPR signaling at the membrane. In obese, diabetic mice the conjugate produced greater weight loss and insulin sensitization than equimolar dosing of the unconjugated peptide and lanifibranor, without the typical PPAR-related cardiac and weight-gain safety signals.