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Semaglutide, tirzepatide and retatrutide: one, two and three receptors

The library records semaglutide at the GLP-1 receptor, tirzepatide at the GLP-1 and GIP receptors, and retatrutide at those two plus the glucagon receptor.[1],[2],[3]

All three are fatty-acid-modified peptides whose sequences and modifications are described in the FDA substance registry.[4],[5],[6]

This overview lines those records up in one table and links to the two paired pages for detail; it ranks none of the three.

Identity side by side

AttributeSemaglutideTirzepatideRetatrutide
FDA UNII[4],[5],[3]53AXN4NNHXOYN3CCI6QENOP2Y096GV
Residues[4],[5],[3]313939
Residue at position 2[4],[5],[3]2-methylalanine2-methylalanine2-methylalanine
Lipidated lysine (registry numbering)[4],[5],[3]202017
Diacid chain named in the registry[4],[5],[3]17-carboxyheptadecanoyl (C18)icosanedioyl (C20)19-carboxynonadecanoyl (C20)
Receptors recorded[1],[2],[3]GLP-1RGIPR, GLP-1RGLP-1R, GIPR, GCGR
Classification (library)[1],[2],[3]GLP-1 receptor agonistDual hormone receptor agonist (GIPR, GLP-1R)Triple hormone receptor agonist (GCGR, GIPR, GLP-1R)
U.S. regulatory entry[7],[8],[9]Drugs@FDA applicationsDrugs@FDA applicationsFDA statement: no approved drug contains it

How does receptor coverage change across the three?

The GLP-1 receptor is the single target that appears in all three records.[1],[2],[3]

The GIP receptor enters with tirzepatide and stays with retatrutide, and the glucagon receptor is recorded for retatrutide alone.[2],[3],[10]

Published cryo-EM work places tirzepatide at two of these receptors and retatrutide at all three.[11],[12],[13]

A 2017 structure of the GLP-1 receptor in its activated, G protein-bound state gives a reference picture of the one receptor every record shares.[14]

Where do the three chemistries overlap and diverge?

Every one of the three registry records carries 2-methylalanine at position 2.[4],[5],[3]

Semaglutide is the short member at 31 residues; the other two are 39 residues long.[4],[5],[3]

Semaglutide and tirzepatide carry their diacid on lysine 20, while retatrutide carries it on lysine 17.[4],[5],[3]

By the registry names, semaglutide's chain is an 18-carbon diacid, and the chains on tirzepatide and retatrutide are 20-carbon diacids.[4],[5],[3]

How do the three regulatory entries differ?

Two of the entries cite Drugs@FDA application numbers and the third cites an FDA statement, so the three are not interchangeable.[7],[8],[9]

An FDA approved drug product containing semaglutide 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 209637, NDA 213051, NDA 215256 and NDA 218316. 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.

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.

What is not being compared?

Different laboratories characterised the three molecules in different assay systems, and none of their receptor figures is merged into an ordering here.[15],[16],[10]

Sequence-level detail sits on the retatrutide-versus-tirzepatide and tirzepatide-versus-semaglutide pages, and outcome data sit on each compound page.

Limitations

Counting receptors describes breadth of recorded pharmacology, not the size or direction of any effect.

The chain lengths quoted here are read from registry names and are not measurements of any material.[4],[5],[3]

Compound profiles

References

  1. Semaglutide research profile, PepGenex Science (identity and records, with their sources).
  2. Tirzepatide research profile, PepGenex Science (identity and records, with their sources).
  3. Retatrutide research profile, PepGenex Science (identity and records, with their sources).
  4. U.S. FDA Global Substance Registration System (GSRS), Semaglutide, UNII 53AXN4NNHX. UNII 53AXN4NNHX · CAS 910463-68-2
  5. U.S. FDA Global Substance Registration System (GSRS), Tirzepatide, UNII OYN3CCI6QE. UNII OYN3CCI6QE · CAS 2023788-19-2
  6. U.S. FDA Global Substance Registration System (GSRS), Retatrutide, UNII NOP2Y096GV. UNII NOP2Y096GV · CAS 2381089-83-2
  7. Drugs@FDA, Applications NDA 209637, NDA 213051, NDA 215256 and NDA 218316. Checked 2026-09-24
  8. Drugs@FDA, Applications NDA 215866 and NDA 217806. Checked 2026-09-24
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. Zhang Y, Sun B, Feng D, et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature. 2017;546(7657):248-253. PMID 28538729 · DOI 10.1038/nature22394 · PMC5587415
  15. Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015;58(18):7370-7380. PMID 26308095 · DOI 10.1021/acs.jmedchem.5b00726
  16. 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