Retatrutide (LY3437943): The Pharmacology of a Triple Receptor Agonist

Retatrutide, known in its discovery work as LY3437943, is a synthetic peptide designed to act on three receptors of the glucagon receptor family: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR).

The discovery paper

Coskun and colleagues described the molecule in Cell Metabolism in 2022, in a paper titled LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. The work characterises the compound's activity at each of the three receptors in vitro and reports studies in animal models, followed by early clinical pharmacology.

Why a "triple agonist" is chemically interesting

The three receptors bind closely related endogenous peptides. Designing one sequence with balanced activity across all three is a medicinal-chemistry challenge, typically involving amino acid substitutions and a fatty-acid modification that extends the molecule's half-life by promoting albumin binding.

Analytical considerations

• Lipidated peptide. The fatty-acid side chain changes chromatographic behaviour, so HPLC methods are adapted for more hydrophobic analytes.
• Larger molecule. At around 39 residues plus the lipid moiety, identity confirmation by mass spectrometry and careful assessment of related impurities are particularly relevant.

Retatrutide supplied by ICU RESEARCH is for laboratory research use only and is not intended for human use.