Research notes
Multi-Receptor Agonists in Laboratory Research: Dual and Triple Hormone Receptor Designs (GIP, GLP-1, and Glucagon)
A reference for laboratories working with peptides described in the literature as agonists at more than one of the GIP, GLP-1 and glucagon receptors. It covers what the receptors are, how the published work classifies the compounds by receptor set, and what the word agonist means in that work. It does not cover physiological effects or any use of the material.
Three receptors, two incretins
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two incretin hormones: peptides secreted by the gut whose receptors, GIPR and GLP-1R, are class B G-protein-coupled receptors. Glucagon is a pancreatic peptide hormone whose receptor, GCGR, is also a class B G-protein-coupled receptor. Glucagon is not an incretin, and a description that groups all three as incretins is wrong. The accurate description of a compound acting at all three is a GIP, GLP-1 and glucagon receptor agonist, or a triple-hormone receptor agonist.
The three receptors are structurally related and share the same general activation mechanism, which is why single peptides can be engineered to act at more than one of them. The three native hormones themselves are selective for their own receptors.
Single, dual and triple designs as classified in the literature
Single-receptor agonists act at one receptor. NN9535 (semaglutide) is described in the literature as a 31-residue analogue of human GLP-1 acting at the GLP-1 receptor.
Dual agonists act at two receptors. LY3298176 (tirzepatide) is described as a 39-residue single-chain peptide built on the GIP sequence, acting at both the GIP receptor and the GLP-1 receptor.
Triple agonists act at three receptors. LY3437943 is described as a 39-residue single-chain peptide acting at the GIP receptor, the GLP-1 receptor and the glucagon receptor concurrently. The primary characterisation is Coskun et al., Cell Metabolism, 2022.
LY3437943 research peptide · LY3298176 research peptide · NN9535 research peptide
What agonist means in this literature
In the published characterisation of these compounds, agonist activity is established in vitro: the peptide is applied to cultured cells expressing one receptor, and receptor activation is measured, most often as cyclic AMP accumulation. Potency at each receptor is reported as an EC50, and the ratio of potencies across receptors is described as the compound's balance. That balance is a design choice made during the medicinal chemistry programme and is reported in the primary paper for each compound.
A statement that a compound is an agonist at a receptor is therefore a statement about receptor binding and activation in a cell-based assay. It is not a statement about what the compound does in an organism, and this site makes no such statement about any material it sells.
Common design features
The dual and triple agonists in this class share several features described in their primary papers: a backbone derived from the GIP sequence rather than the GLP-1 sequence; aminoisobutyric acid substitutions, including at the position where the native incretins are cleaved by dipeptidyl peptidase-4; and a fatty diacid side chain attached through a linker to a lysine residue. Each feature is a structural fact about the molecule and is reported, with the specific positions, in the cited literature rather than here.
What this page does not cover
This page describes receptors and molecular design. It does not describe physiological effects, clinical findings, or any use of the material in humans or animals. The clinical papers on these compounds are cited on the product pages as published work by others; their findings are not summarised on this site. The material sold here is lyophilized peptide for laboratory research, in unlabeled vials, to businesses only.
Primary literature
Listed so a reader can go to the source. These papers describe the compounds as studied by others; they are not claims about any material sold here.
- Coskun T, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept Cell Metabolism, 2022
- Coskun T, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept Molecular Metabolism, 2018