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Retatrutide vs tirzepatide: sequence, receptors and records

Retatrutide (LY3437943) and tirzepatide (LY3298176) are lipidated peptides of 39 residues each, and the published record places both at the GIP and GLP-1 receptors.[1],[2],[3],[4]

Where they part is a third receptor: retatrutide is also reported as an agonist at the glucagon receptor, while tirzepatide's discovery paper describes activity at the two incretin receptors.[3],[5],[4]

Below, the structures, receptor pharmacology and U.S. regulatory entries of the two molecules are set out side by side, with no study outcome placed against another.

Identity side by side

AttributeRetatrutideTirzepatide
Development code[6],[7]LY3437943LY3298176
FDA UNII[6],[2]NOP2Y096GVOYN3CCI6QE
CAS Registry Number[6],[7]2381089-83-22023788-19-2
Length and sequence (registry, one-letter)[6],[2]39 residues: YAQGTFTSDYSILLDKKAQAAFIEYLLEGGPSSGAPPPS39 residues: YAEGTFTSDYSIGLDKIAQKAFVQWLIAGGPSSGAPPPS
Non-coded residues[6],[2]2-methylalanine at 2 and 20; 2-methyl-L-leucine at 132-methylalanine at 2 and 13
Lipidated residue[6],[2]Lysine 17: 19-carboxynonadecanoyl (C20 diacid) via γ-glutamyl and [2-(2-aminoethoxy)ethoxy]acetyl linkersLysine 20: icosanedioyl (C20 diacid) via a γ-glutamyl–bis(iminobis(ethylenoxy)acetyl) linker, as the registry names it
C-terminus[6],[2]AmideSerinamide
Receptors recorded[6],[7]GLP-1 receptor; GIP receptor; glucagon receptorGIP receptor; GLP-1 receptor
Receptor structures published[5],[8],[9]Cryo-EM with GLP-1R, GIPR and GCGR (each with Gs)Cryo-EM with GIPR and GLP-1R
U.S. regulatory entry[10],[11]FDA statement (Drug Alerts and Statements)Drugs@FDA, NDA 215866 and NDA 217806

How do the two sequences differ?

In the FDA substance registry's one-letter sequences, the two peptides match at 30 of their 39 positions and end in the same eleven residues, GGPSSGAPPPS.[6],[2]

Each opens with tyrosine followed by 2-methylalanine, but the other non-coded residues sit in different places: tirzepatide carries a second 2-methylalanine at position 13, whereas retatrutide carries 2-methyl-L-leucine at 13 and 2-methylalanine at 20.[6],[2]

The fatty diacid chain hangs from lysine 20 in tirzepatide and from lysine 17 in retatrutide, and the registry describes a 20-carbon diacid joined through a γ-glutamyl spacer in both records.[6],[2]

The tirzepatide structural work regards both the fatty acid modification and the amino acid sequence as what determines how that molecule engages its receptors.[9]

Which receptors does the literature record for each?

Retatrutide's discovery work reported agonism, measured in cell-based assays, at GCGR, GIPR and GLP-1R.[3]

Tirzepatide's discovery work reported that it activated both GIP and GLP-1 receptor signalling in vitro, and no glucagon-receptor activity is attributed to it here.[4]

For retatrutide, cryo-electron microscopy has resolved the peptide bound to each of its three receptors in complex with the Gs protein.[5]

For tirzepatide, two independent 2022 studies reported cryo-electron microscopy structures at GIPR and at GLP-1R.[8],[9]

All of these targets are class B1 G protein-coupled receptors, the family the retatrutide record names for its three receptors.[6]

What does each U.S. regulatory record say?

The two regulatory entries are of different kinds: one is an FDA statement about an unapproved compound, the other a pair of Drugs@FDA application numbers.[10],[11]

The U.S. FDA states that no FDA-approved drug contains retatrutide. Source: U.S. FDA, Drug Alerts and Statements, https://www.fda.gov/drugs/drug-alerts-and-statements/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss, content current as of 2026-09-01. Checked 2026-09-24.

An FDA approved drug product containing tirzepatide exists. PepGenex research materials are not that product, are not FDA approved, and are not for human or veterinary use. Source: Drugs@FDA, Applications NDA 215866 and NDA 217806. Checked 2026-09-24.

What does this comparison leave out?

Receptor activity values for the two molecules are not set against each other here, because the figures cited come from separate publications using separate assay systems.[4],[3]

Animal and clinical findings for each compound stay on that compound's own page and are not paired on this one.

Limitations

Receptor agonism in cell assays and cryo-EM structures describe molecular binding under laboratory conditions and establish no effect in a living organism.[6]

Registry sequences describe each reference substance; they are not an analysis of any supplied lot.[2],[6]

Compound profiles

References

  1. U.S. FDA Global Substance Registration System (GSRS), Retatrutide, UNII NOP2Y096GV. UNII NOP2Y096GV · CAS 2381089-83-2
  2. U.S. FDA Global Substance Registration System (GSRS), Tirzepatide, UNII OYN3CCI6QE. UNII OYN3CCI6QE · CAS 2023788-19-2
  3. Coskun T, Urva S, Roell WC, et al. Cell Metab. 2022;34(9):1234-1247.e9. PMID 35985340 · DOI 10.1016/j.cmet.2022.07.013
  4. Coskun T, Sloop KW, Loghin C, et al. Mol Metab. 2018;18:3-14. PMID 30473097 · DOI 10.1016/j.molmet.2018.09.009 · PMC6308032
  5. Li W, Zhou Q, Cong Z, et al. Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Cell Discov. 2024;10(1):77. PMID 39019866 · DOI 10.1038/s41421-024-00700-0 · PMC11255275
  6. Retatrutide research profile, PepGenex Science (identity and records, with their sources).
  7. Tirzepatide research profile, PepGenex Science (identity and records, with their sources).
  8. Zhao F, Zhou Q, Cong Z, et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun. 2022;13(1):1057. PMID 35217653 · DOI 10.1038/s41467-022-28683-0 · PMC8881610
  9. Sun B, Willard FS, Feng D, et al. Structural determinants of dual incretin receptor agonism by tirzepatide. Proc Natl Acad Sci U S A. 2022;119(13):e2116506119. PMID 35333651 · DOI 10.1073/pnas.2116506119 · PMC9060465
  10. U.S. FDA, Drug Alerts and Statements, https://www.fda.gov/drugs/drug-alerts-and-statements/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss, content current as of 2026-09-01. Checked 2026-09-24
  11. Drugs@FDA, Applications NDA 215866 and NDA 217806. Checked 2026-09-24