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 and 13 with α-aminoisobutyric acid (Aib), which prevents degradation by dipeptidyl peptidase-4 (DPP-4) at position 2. At position 20, a lysine residue is site-specifically acylated with a C20 fatty diacid (eicosanedioic acid) via a γGlu-(AEEA-AEEA) linker (γ-glutamic acid and two 8-amino-3,6-dioxaoctanoic acids) to promote albumin binding and prolong the half-life (Figure 1).
Figure 1. Structure of Tirzepatide
Native incretin hormones like GIP and GLP-1 have poor pharmacokinetics, making them susceptible to enzymatic degradation, renal clearance, and rapid receptor-mediated clearance. Tirzepatide overcomes this through strategic amino acid substitutions and the site-specific fatty acid conjugation mentioned above.The half-life is extended 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 Aib, 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 regarding 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.