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 (Friedrichsen).
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 (Lewis).
Semaglutide is chemically similar to human GLP-1. The first six amino acids of GLP-1 are missing. Substitutions are made at GLP positions 8 and 34 (semaglutide positions 2 and 28), where alanine and lysine are replaced by 2-aminoisobutyric acid and arginine, respectively.The substitution of the alanine prevents chemical breakdown by dipeptidyl peptidase-4. The lysine at GLP position 26 (semaglutide position 20) has a long chain attached, ending with a chain of 18 carbon atoms and a carboxyl group (Figure 1). This increases the drug's binding to blood protein (albumin), which enables longer presence in the blood circulation. Semaglutide's half-life in the blood is about seven days (Xu).
Figure 1. Structure of Semaglutide
Native GLP-1 is rapidly degraded by DPP-4 and cleared from circulation, but semaglutide overcomes this through site-specific conjugation at the lysine residue with a PEGylated C18 fatty diacid via a linker. This modification promotes albumin binding, protects against enzymatic degradation, and extends the half-life to approximately one week-enabling once-weekly dosing with demonstrated benefits in glucose control and weight loss (Xu).
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.