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Semaglutide, tirzepatide and retatrutide: structural comparison
Three engineered incretin analogues, compared on sequence, receptor characterization and supplied format.
Semaglutide, tirzepatide and retatrutide are all engineered peptides of the incretin-analogue class, built on the glucagon superfamily scaffold. They are frequently discussed together because they represent successive generations of the same design approach, and the differences between them are structural and specific.
This page compares them on the properties that can be stated as fact: how many residues each has, which receptor families each is characterized against, what modifications each carries, and what formats are stocked. It does not rank them, because rank is not a structural property.
| Property | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Residue count | 31 amino acids | 39 amino acids | 39 amino acids |
| Parent sequence | GLP-1 | GIP backbone | GIP-based, engineered for triple engagement |
| Receptor families characterized against | GLP-1 | GIP and GLP-1 | GIP, GLP-1 and glucagon |
| Lipid modification | C18 diacid at lysine 26 | C20 diacid at lysine 20 | Fatty acid modification |
| Non-proteinogenic residues | AIB at position 8 | AIB at positions 2 and 13 | AIB present in sequence |
| Development code | NN9535 | LY3298176 | LY3437943 |
| HEEZ catalogue shorthand | GLP-1 SM | GLP-2 TZ | GLP-3 RT |
| Strengths stocked | 10 mg | 10 mg | 10 mg and 20 mg |
| Supply form | Lyophilized powder | Lyophilized powder | Lyophilized powder |
| Storage | Refrigerated, protected from light | Refrigerated, protected from light | Refrigerated, protected from light |
Receptor breadth as a structural property
The clearest structural difference between the three is how many receptor families each is characterized against. Semaglutide engages one — the GLP-1 receptor. Tirzepatide is characterized against two, GIP and GLP-1. Retatrutide is characterized against three, adding the glucagon receptor.
This is a classification of the molecules, not a statement about what follows from it. Engaging more receptor families is a design property of the sequence, arising from which residues occupy the positions that determine selectivity between related receptors in the same family.
The three receptors involved are all class B G-protein-coupled receptors and all bind peptides of the glucagon superfamily, which is why a single engineered sequence can be designed to engage several of them. Their close structural relationship is what makes multi-receptor design tractable at all.
Sequence lineage
Semaglutide is built on the GLP-1 sequence directly — 31 residues, closely following the native peptide with three deliberate changes. Its lineage is the most straightforward of the three.
Tirzepatide is built on the GIP backbone rather than GLP-1, which is why its residue count is 39 rather than 31 and why its generic name carries the -tide suffix rather than the -glutide stem shared by GLP-1 analogues. That naming difference reflects a real structural distinction.
Retatrutide is also 39 residues and shares the general architecture, engineered further so that glucagon receptor engagement is added to the profile. Sharing a residue count with tirzepatide does not make the sequences the same; it reflects a common design starting point.
Modifications and why they are there
All three carry a fatty diacid chain and at least one alpha-aminoisobutyric acid substitution. These are the two standard interventions in this class and they address different problems.
AIB is placed at positions vulnerable to dipeptidyl peptidase-4, which cleaves native incretins rapidly at the N-terminal end. The residue's additional methyl groups obstruct the cleavage site sterically. Tirzepatide carries two such substitutions where semaglutide carries one.
The diacid chain — C18 on semaglutide, C20 on tirzepatide — promotes reversible albumin binding, which slows clearance. Chain length differs between the compounds but the mechanism is the same, and in each case the lipid governs persistence rather than receptor engagement.
Formats and handling
All three are supplied as lyophilized powder in vials, ambient-stable in transit and refrigerated on arrival. Handling does not differ meaningfully between them: the same reconstitution arithmetic applies, and bacteriostatic water is the usual diluent where a vial is entered more than once.
The one format difference is that retatrutide is stocked in two vial masses, 10 mg and 20 mg, while semaglutide and tirzepatide are each stocked in a single 10 mg format. That affects the concentration achievable for a given diluent volume and nothing else.
Because all three are comparatively heavy molecules, a given mass represents fewer molar units than the same mass of a short peptide. Protocols specified in molar terms should use the molecular weight from each compound's certificate of analysis.
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