Semaglutide is a medication that belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists. It mimics the action of the natural hormone GLP-1, which is produced in the body after eating, signaling the pancreas to release insulin in response to high blood sugar levels. Semaglutide works by reducing appetite, delaying gastric emptying, increasing insulin release, and lowering the amount of glucagon released. At higher doses, semaglutide can be used for chronic weight management in adults who are obese or overweight and have at least one weight-related comorbidity.
Semaglutide was developed by Novo Nordisk and approved for medical use in the US in 2017, It is sold by Novo Nordisk under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight management and weight loss. Each brand is FDA-approved for different conditions.
Semaglutide is structurally similar to human GLP-1, but lacks the first six amino acids of the native peptide. Substitutions are made at GLP-1 positions 8 and 34, where alanine and lysine are replaced by α-aminoisobutyric acid (Aib) and arginine, respectively. The substitution of the alanine with Aib protects against enzymatic degradation by dipeptidyl peptidase-4 (DPP-4). The lysine at GLP-1 position 26 is acylated with a C18 fatty diacid via a γGlu-(AEEA-AEEA) linker (γ-glutamic acid and two 8-amino-3,6-dioxaoctanoic acids) to increase the drug's binding to blood albumin. This results in an extended circulation time, with a half-life of approximately seven days for once-weekly dosing (Xu).
Figure 1. Structure of Semaglutide
Semaglutide can be made by solid-phase peptide synthesis with site-specific incorporation of non-natural amino acids such as α-aminoisobutyric acid (Aib) and conjugation of the lipid attached to the lysine residue of the peptide, as depicted in Figure 2.
Figure 2. Synthesis of Semaglutide
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Friedrichsen, M., Breitschaft, A., Tadayon, S., Wizert, A., & Skovgaard, D. (2021). The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes, Obesity and Metabolism, 23(3), 754-762.
Lewis, A. L., McEntee, N., Holland, J., & Patel, A. (2022). Development and approval of rybelsus (oral semaglutide): ushering in a new era in peptide delivery. Drug delivery and translational research, 12(1), 1-6.
Xu, Y., & Kuipers, O. P. (2025). Design and Biosynthesis of Ornithine 8-Containing Semaglutide Variants with a Click Chemistry-Modifiable Position 26. ACS Synthetic Biology, 14(5), 1790-1801.