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Tirzepatide vs semaglutide: structure and receptor records

Semaglutide was designed as a GLP-1 analogue aimed at high serum albumin affinity and full stability against metabolic degradation, and tirzepatide is described as a fatty acid modified peptide with activity at two incretin receptors.[1],[2]

The GIP receptor is the pathway difference in the record: it is listed for tirzepatide and absent from semaglutide's recorded targets.[3],[4]

This page compares sequence, modification, receptor records and regulatory entries, and it reports no trial figure for either molecule.

Identity side by side

AttributeTirzepatideSemaglutide
Development code[5],[6]LY3298176NN9535; NNC 0113-0217
FDA UNII[5],[6]OYN3CCI6QE53AXN4NNHX
CAS Registry Number[3],[4]2023788-19-2910463-68-2
Length and sequence (registry, one-letter)[5],[6]39 residues: YAEGTFTSDYSIGLDKIAQKAFVQWLIAGGPSSGAPPPS31 residues: HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG
N-terminal residue[5],[6]TyrosineHistidine
Non-coded residues[5],[6]2-methylalanine at 2 and 132-methylalanine at 2
Lipidated residue[5],[6]Lysine 20: icosanedioyl (C20 diacid) chainLysine 20: 17-carboxyheptadecanoyl (C18 diacid) chain via γ-glutamyl and two [2-(2-aminoethoxy)ethoxy]acetyl units
Relation to a native hormone (as published)[7],[1]Activates GIPR in a way that closely resembles native GIPHuman GLP-1 with Aib8 and Arg34, derivatised at Lys26 (GLP-1 numbering)
Receptors recorded[3],[4]GIP receptor; GLP-1 receptorGLP-1 receptor
U.S. regulatory entry[8],[9]Drugs@FDA, NDA 215866 and NDA 217806Drugs@FDA, NDA 209637, 213051, 215256 and 218316

How are the two molecules built?

Semaglutide's discovery paper describes it as human GLP-1 carrying two substitutions, 2-methylalanine at position 8 and arginine at position 34, with a derivatised lysine at 26 in the hormone's own numbering.[1]

The substance registry numbers the same chain from 1 to 31, which puts those features at positions 2, 28 and 20.[6]

Tirzepatide runs eight residues longer and opens with tyrosine where semaglutide opens with histidine.[5],[6]

Both place 2-methylalanine at registry position 2 and a fatty diacid on the lysine at registry position 20, with the registry naming an 18-carbon diacid for semaglutide and a 20-carbon one for tirzepatide.[5],[6]

Which receptor pathways are recorded?

Semaglutide's recorded target in this library is the GLP-1 receptor alone, and its design work names GLP-1 receptor affinity and serum albumin binding as the properties it was optimised for.[4],[1]

Tirzepatide is recorded at the GIP receptor and the GLP-1 receptor.[3],[2]

A 2022 structural study reports that tirzepatide resembles native GIP in the way it activates GIPR but differs markedly from native GLP-1 in the way it activates GLP-1R.[7]

A second 2022 cryo-electron microscopy study, which resolved tirzepatide at GIPR and GLP-1R, refers to semaglutide as a monoagonist by way of contrast.[10]

What do the U.S. regulatory records say?

Each molecule has approved applications in Drugs@FDA, and the lines below are printed from the library's regulatory table without naming any indication.[8],[9]

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.

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.

What is outside the scope of this comparison?

The published GLP-1 receptor affinity for semaglutide was measured against liraglutide rather than tirzepatide, so no cross-compound affinity figure is given.[1]

Trial results for the two molecules come from different programmes, populations and durations, and none of them is set beside another.

Limitations

A receptor listed for a compound records what laboratory studies measured; it does not describe what the molecule does in an organism.[4],[3]

The approved products in Drugs@FDA are not PepGenex research materials, and nothing in this comparison transfers to a research lot.[9],[8]

Compound profiles

References

  1. 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
  2. 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
  3. Tirzepatide research profile, PepGenex Science (identity and records, with their sources).
  4. Semaglutide research profile, PepGenex Science (identity and records, with their sources).
  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), Semaglutide, UNII 53AXN4NNHX. UNII 53AXN4NNHX · CAS 910463-68-2
  7. 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
  8. Drugs@FDA, Applications NDA 215866 and NDA 217806. Checked 2026-09-24
  9. Drugs@FDA, Applications NDA 209637, NDA 213051, NDA 215256 and NDA 218316. Checked 2026-09-24
  10. 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