Tirzepatide is a medication that belongs to a new class of drugs known as dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. It mimics the action of the natural incretin hormones GIP and GLP-1, which are released after eating and help regulate blood sugar levels by stimulating insulin secretion, suppressing glucagon release, slowing gastric emptying, and reducing appetite. By activating both receptors, Tirzepatide offers enhanced metabolic benefits compared to GLP-1 agonists alone (Nauck).
Tirzepatide was developed by Eli Lilly and approved for medical use in the US in 2022. It is marketed under the brand name Mounjaro for the treatment of type 2 diabetes and under the brand name Zepbound for weight management and weight loss (Nauck).
Tirzepatide is a synthetic peptide modeled after the native GIP hormone but modified to also activate the GLP-1 receptor. It consists of 39 amino acids with several substitutions that enhance stability and dual receptor activity. A key modification is the substitution of alanine at position 2 with D-alanine, which prevents degradation by dipeptidyl peptidase-4. At position 20, a lysine residue is site-specifically acylated with a C20 fatty diacid (icosanedioic acid) via a γ-glutamic acid linker and a short polyethylene glycol (PEG) spacer (Figure 1).
Figure 1. Structure of Tirzepatide
Native incretin hormones like GIP and GLP-1 are rapidly degraded by DPP-4 and cleared from circulation, but Tirzepatide overcomes this through strategic amino acid substitutions and site-specific conjugation at the lysine-20 residue with a PEGylated C20 fatty diacid via a γ-glutamic acid linker. These modifications promote albumin binding, protect against enzymatic degradation, and extend the half-life to approximately five days-supporting once-weekly dosing with demonstrated benefits in glucose control and weight management (Gare).
Tirzepatide can be made by solid-phase peptide synthesis with site-specific incorporation of non-natural amino acids such as D-alanine, followed by conjugation of a lipid moiety-derived from 20-(tert-butoxy)-20-oxoicosanoic acid-to a lysine residue via a γ-glutamic acid linker and PEG spacer, as shown in Figure 2.
Figure 2. Synthesis of Tirzepatide
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Compounds such as Semaglutide, Tirzepatide, and the investigational Retatrutide highlight the therapeutic potential of strategic peptide conjugation in treating metabolic diseases. BroadPharm offers research-grade versions of these and other peptide-based therapeutics-ideal for use as reference standards, assay controls, or in early-stage development and mechanistic studies.
Gare, C. L., White, A. M., & Malins, L. R. (2025). From lead to market: chemical approaches to transform peptides into therapeutics. Trends in Biochemical Sciences.
Nauck MA, D'Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol. 2022 Sep 1;21(1):169. doi: 10.1186/s12933-022-01604-7. PMID: 36050763; PMCID: PMC9438179.