Comparison
Semaglutide vs Tirzepatide vs Retatrutide
Three acylated incretin analogues of increasing receptor breadth — single, dual and triple receptor activity — compared by residue count, mass and structural class.
Side by side
| Property | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| CAS number | 910463-68-2 | 2023788-19-2 | 2381089-83-2 |
| Molecular formula | C187H291N45O59 | C225H348N48O68 | C221H342N46O68 |
| Average molecular weight | 4,113.58 g/mol | 4,813.45 g/mol | 4,731.40 g/mol |
| Amino-acid count | 31 | 39 | 39 |
| Peptide class | acylated GLP-1 analogue | lipidated 39-residue peptide analogue | lipidated 39-residue peptide analogue |
| Physical form | Lyophilized powder | Lyophilized powder | Lyophilized powder |
| Research area | Metabolic research | Metabolic research | Metabolic research |
| Solubility | Soluble in sterile or bacteriostatic water; consult the lot COA for solvent guidance | Soluble in sterile or bacteriostatic water; consult the lot COA for solvent guidance | Soluble in sterile or bacteriostatic water; consult the lot COA for solvent guidance |
| Primary sequence | — | — | — |
One design, three receptor breadths
These three represent successive generations of the same engineering programme, and the trend across them is receptor breadth rather than molecular size.
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Residues | 31 | 39 | 39 |
| Mass (g/mol) | 4,113.58 | 4,813.45 | 4,731.4 |
| Receptors | GLP-1 | GIP, GLP-1 | GIP, GLP-1, glucagon |
| Lipid | C18 diacid | C20 diacid | Lipidated |
Note that mass does not increase monotonically with receptor breadth: retatrutide engages three receptors and is lighter than tirzepatide, which engages two. Molecular size and functional complexity are not the same axis.
The shared architecture
All three use the same two-part stabilization strategy, and it is worth stating because it explains why they look alike analytically.
Aib substitution blocks dipeptidyl peptidase-4, the enzyme that inactivates native GLP-1 within minutes.
Lipidation through a linker provides reversible serum albumin binding, protecting the molecule from renal filtration and creating a circulating reservoir.
Neither modification alone suffices — one addresses enzymatic degradation, the other renal clearance — and the combination is the solved problem being reapplied across the family, with design effort going into receptor selectivity instead.
Why sequences are not published
A plain residue string would omit the Aib substitutions, the acylation site, the linker chemistry and the fatty acid — most of what distinguishes each molecule. Identity confirmation for all three rests on mass spectrometry against the complete modified structure.
Shared handling profile
All three are strongly hydrophobic for their length, retain late on reversed-phase columns, adsorb to plastic, and — unusually — aggregate more readily in concentrated solution than dilute, because the exposed lipid seeks a hydrophobic environment and often finds another molecule of the same compound. Reconstitute gently, aliquot immediately, and prepare working dilutions fresh.