Tirzepatide (LY3298176): Designing a Dual GIP and GLP-1 Receptor Agonist

Tirzepatide, first described as LY3298176, is a synthetic peptide engineered to activate two incretin receptors: the GIP receptor and the GLP-1 receptor.

The discovery work

Coskun and colleagues reported the molecule in Molecular Metabolism in 2018, in 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. The paper describes the peptide's design on the basis of the GIP sequence, its activity at both receptors in cell-based assays, studies in animal models, and early clinical pharmacology.

Design features

The authors describe a sequence based on native GIP with modifications that confer GLP-1 receptor activity, together with a C20 fatty diacid moiety that supports binding to albumin and a prolonged half-life. This combination of sequence engineering and lipidation is now a common strategy for long-acting peptide hormones.

Relationship to retatrutide

Retatrutide (LY3437943) extends the same concept by adding glucagon-receptor activity, creating a triple agonist. Comparing the two discovery papers is a useful way to understand how receptor selectivity is tuned within this peptide family.

Analytical considerations

Like other lipidated peptides, tirzepatide requires HPLC conditions suitable for hydrophobic analytes, and mass-spectrometric confirmation of the intact molecule including its fatty-acid modification.

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