GLP-3 (Retatrutide) 20mg

GLP-3 (Retatrutide) is a 39-residue lipopeptide studied as a triple agonist at the GLP-1, GIP and glucagon receptors. Three positions carry non-standard residues: alpha-aminoisobutyric acid at 2 and 20, and alpha-methyl-leucine at 13. All three are modelled explicitly in the PepXtide structural library.

One honest caveat about the 3D model: the C20 fatty diacid on Lys17 is a lipid tail and is not drawn, so the mass shown by the viewer is the peptide backbone alone rather than the 4,731.33 g/mol figure for the complete molecule.

Like its dual-agonist relative in this catalogue, the compound is built on a GIP backbone rather than a GLP-1 one, and was developed at Eli Lilly, with the originating characterisation published in 2022. The stated design intent was to protect the sequence from dipeptidyl peptidase IV recognition and to raise activity at the GIP and glucagon receptors while retaining activity at the GLP-1 receptor.

The pattern of non-standard residues differs from the dual agonist in a way that is easy to get wrong. Here the two alpha-aminoisobutyric acids sit at positions 2 and 20, and position 13 carries alpha-methyl-leucine rather than a second aminoisobutyric acid. The acylation site also differs: the diacid hangs from lysine 17, not lysine 20, and reaches the chain through a gamma-glutamate and a single oligoethylene-glycol spacer rather than two. The diacid itself is the same C20 eicosanedioic acid in both compounds, and it is the albumin-binding element that extends residence. The C-terminus is a serine amide.

All three receptors are class B1 G-protein-coupled receptors. Reported cyclic AMP half-maximal concentrations are roughly 0.064 nanomolar at the GIP receptor, 0.775 nanomolar at the GLP-1 receptor and 5.79 nanomolar at the glucagon receptor, so the compound is not equipotent across its three targets; relative to the endogenous ligands it is described as more potent at the GIP receptor and somewhat less potent at the other two. Published binding constants appear mainly on vendor pages rather than in primary literature and are not reproduced here.

Structural and mechanistic work uses cryo-electron microscopy of the compound bound to each of the three receptors in complex with Gs, alongside molecular dynamics and alanine-scanning mutagenesis of the receptors, with cyclic AMP accumulation read out against the mutant panel. Analytical characterisation in the published work is by validated liquid chromatography with high-resolution mass spectrometry.

A specification caution that catches people out. A regulatory substance registry lists a mass near 4,092 daltons for this compound, flagged as an estimate; that figure is the unmodified 39-residue backbone, excluding the lipid, the linker and the C-terminal amide. The figure published on this page, 4,731.33 g/mol, is the complete molecule.