Peptide News Digest

#Dimarchi

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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.

Research · View digest

STAT News: GLP-1 Pioneers DiMarchi and Tschöp Propose Dropping GLP-1 as a Drug Target for Obesity

Richard DiMarchi and Matthias Tschöp — whose work enabled Eli Lilly's Zepbound and the modern GLP-1 class — published a peer-reviewed draft paper arguing that targeting GIP and glucagon receptors alone, without GLP-1, may deliver comparable weight loss without the nausea and vomiting that plague current therapies. The experimental molecule, backed by BlueWater Biosciences, challenges the central dogma of obesity drug design. Results are preclinical and must still translate to humans.