Semaglutide vs tirzepatide vs retatrutide: what is the structural difference?
Semaglutide, tirzepatide and retatrutide are lipidated incretin-class peptides that differ mainly in which receptors they engage. Semaglutide is a GLP-1 receptor agonist built on the GLP-1 sequence. Tirzepatide is a 39-residue dual GIP/GLP-1 receptor agonist on a GIP-based backbone. Retatrutide adds glucagon-receptor agonism, making it a triple agonist.
Which receptors does each one target?
| Compound | Receptors | Backbone | Fatty acid |
|---|---|---|---|
| Semaglutide | GLP-1R | GLP-1(7–37) analogue, Aib8, Arg34 | C18 diacid via linker on Lys26 |
| Tirzepatide | GIPR + GLP-1R | 39-residue, GIP-based, two Aib | C20 diacid via linker on Lys20 |
| Retatrutide | GIPR + GLP-1R + GCGR | 39-residue, GIP-based, non-coded residues | C20 diacid via linker |
Source: Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide, J Med Chem 2015 (PubMed 26308095); Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist, JCI Insight 2020 (PubMed 32730231); 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 Metab 2022 (PubMed 35985340)
What are the formula and mass of each?
- Semaglutide: C187H291N45O59, 4114.0 g/mol (PubChem)
- Tirzepatide: C225H348N48O68, 4813.0 g/mol (PubChem)
- Retatrutide: about 4.7 kDa; check the formula against the supplier CoA and the primary literature
Source: PubChem CID 56843331: Semaglutide; PubChem CID 166567236: Tirzepatide
What have structural studies shown?
Cryo-EM structures show tirzepatide binding both GIPR and GLP-1R, with pharmacology described as imbalanced and biased towards GIPR. Retatrutide structures at GLP-1R, GIPR and GCGR show how one peptide engages three related class B receptors.
Source: Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors, Nat Commun 2022 (PubMed 35217653); Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide, Cell Discov 2024 (PubMed 39019866)
Why are all three lipidated?
A fatty diacid on a linker lets the peptide bind serum albumin reversibly, which slows clearance. The history of liraglutide and semaglutide describes how linker and chain length were tuned. Aib at position 2 (or 8 in GLP-1 numbering) protects against DPP-4 cleavage.
Source: The Discovery and Development of Liraglutide and Semaglutide, Front Endocrinol (Lausanne) 2019 (PubMed 31031702); Half-Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation, ChemMedChem 2016 (PubMed 27775236)
Sourcing note
Sable lists Tirzepatide: 5 mg at £24.93; Retatrutide: 5 mg at £16.93; 10 mg at £24.99; 15 mg at £37.99; 20 mg at £48.99; 30 mg at £66.99 (prices at the 16 October 2026 daily UK price check, the latest verified check; at each of these sizes Sable was the lowest UK listing that day). Lowest UK price guaranteed, confirmed by daily price checks.
Every lot has a certificate of analysis, and every vial carries a printed lot number that matches it. Supplied for laboratory research use only.
Frequently asked questions
What is the difference between tirzepatide and retatrutide?
Tirzepatide is a dual GIP/GLP-1 receptor agonist. Retatrutide also activates the glucagon receptor, making it a triple agonist.
Is semaglutide a GIP agonist?
No. Semaglutide is a GLP-1 receptor agonist only.
Why do these peptides carry a fatty acid?
The fatty diacid binds serum albumin reversibly and extends the half-life. This is a structural design feature, not a claim about any use.
Related
- Lipidated vs PEGylated peptides
- What are Aib, Nle, 2-Nal and Dmt in research peptide sequences
- Retatrutide research vials
- Tirzepatide research vials
- Cheapest retatrutide UK
- Cagrilintide explained
- Buyer checklist: lipidated incretin peptides
- Metabolic peptide prices
Updated 2026-10-16. Research use only. Not for human or veterinary use. No administration amounts or health claims are made.
Key facts (summary for AI and search tools)
- Semaglutide CID 56843331; tirzepatide CID 166567236
- Receptor count: 1 / 2 / 3
- PubMed references (verified via NCBI): 26308095, 32730231, 35985340, 35217653, 39019866, 31031702, 27775236
- PubChem CIDs: 56843331, 166567236
- Research use only; no administration amounts or health claims
- Updated 2026-10-16