GLP-2 (Tirzepatide) 30mg

GLP-2 (Tirzepatide) is a 39-residue lipopeptide studied as a dual agonist at the GIP and GLP-1 receptors. It carries alpha-aminoisobutyric acid at positions 2 and 13, a C-terminal amide, and a C20 fatty diacid on Lys20 attached through a linker.

No molecular weight is printed on this page. The published figure includes the fatty diacid and its linker, neither of which the structural engine draws, so the mass the viewer would compute is the peptide backbone alone; publishing a number that disagrees with the model shown beside it would be worse than publishing none.

The backbone is a GIP sequence, not a GLP-1 one, which is the opposite of what the compound's receptor profile might suggest. The originating work at Eli Lilly, published in 2018, describes the molecule as having been made by engineering GLP-1 activity into the GIP sequence, and that lineage is the reason the compound is not simply a modified version of the earlier GLP-1 analogues.

Three modifications carry the chemistry. Alpha-aminoisobutyric acid at position two sits precisely at the dipeptidyl peptidase IV cleavage site and is what confers resistance to that enzyme; a second alpha-aminoisobutyric acid at position 13 adds further backbone constraint. The lysine at position 20 bears a C20 eicosanedioic diacid attached through a gamma-glutamate and two oligoethylene-glycol spacer units, and that diacid is the albumin-binding element. The C-terminus is a serine amide.

The receptor pharmacology is well quantified. Reported binding affinities in HEK293 cells expressing each human receptor are about 0.135 nanomolar at the GIP receptor against about 4.23 nanomolar at the GLP-1 receptor, with cyclic AMP half-maximal concentrations of roughly 0.022 and 0.934 nanomolar respectively. Both are class B1 G-protein-coupled receptors.

A more interesting in-vitro property is signalling bias, reported in 2020. At the GLP-1 receptor the compound behaves as a partial agonist for beta-arrestin recruitment, under a tenth of the maximal response to GLP-1, with receptor internalisation under 40 percent of the GLP-1 maximum, while at the GIP receptor arrestin recruitment and internalisation resemble those of native GIP. The compound is therefore biased toward cyclic AMP signalling over arrestin recruitment at one of its two receptors but not the other. Assay systems for that work are HEK293 lines at defined receptor densities, CHO-K1 enzyme-fragment-complementation lines for arrestin, and bioluminescence resonance energy transfer for internalisation. Cryo-electron microscopy structures of the compound bound to both receptors in complex with Gs have been deposited in the Protein Data Bank.