PotM: Semaglutide and Peptide-Based Weight-Loss Drugs

GLP-1 (glucagon-like peptide 1) is a peptide hormone from the incretin family. It helps to regulate digestion and blood sugar levels and is released by the small intestine after eating food. It reduces hunger, promotes the feeling of satiety, inhibits glucagon and stimulates insulin. In this way, GLP-1 helps to maintain the euglycemic state (normal blood glucose levels). In the body, natural incretins are degraded within minutes. Medications which act like incretins are used in the therapy of type 2 diabetes in patients with morbid obesity, when the body mass index (BMI) is over 30. As the GLP-1 analogs are peptides, they need to be injected. A replacement therapy with the original component would require their continuous infusion, which is not only inconvenient for the patient, but also would require gigantic amounts of the synthetic peptide. 

The “magic” trick to achieve feasible treatments was to increase the plasma half-life of the therapeutic peptides by delaying their degradation and by providing a depot with slow release. In this way, the number of injections of such medications may be drastically reduced to once per week or even just one per month. Studies are under way to corroborate evidence that GLP-1 agonists also protect patients from other life-threatening conditions like heart disease and kidney failure. 

Semaglutide (Ozempic®, Wegovy®) and similar APIs like Tirzepatide (Zepbound®, Mounjaro®) have been approved for the treatment of morbid obesity (adipositas) and type II diabetes (insulin resistance) and are also prescribed as lifestyle drugs for weight loss. They all work best when changes in lifestyle are initiated and observed, e.g., a calory-restricted diet and the engagement in regular and significant physical activity. 

Chemical structure of Semaglutide: The amino acids differing from active GLP-1 are highlighted (A2Aib; K28R). The side chain of the lysine at position 20 is extended with a spacer/linker made of two amino(ethoxy(ethoxy)acetyl (AEEA, OEG, O2Oc) units, γ-glutamate and 1,18 octadecanoic acid which acts as albumin anchor. 

In the following, we’d like to illustrate the principle of long-acting peptides using the example of Semaglutide: Semaglutide acts as a GLP-1 receptor agonist, mimicking the natural ligand GLP-1, which is processed from the pro-glucagon peptide. Following the structure of the active human GLP-1 (7-37), it has 31 amino acids. The alanine in position 2 (8) has been exchanged against α-aminobutyric acid (Aib), conferring resistance to degradation by the protease dipeptidyl-peptidase 4 (DPP-4). The other modification is the exchange of the Arg at position 20 (26) against Lys, where a side chain is attached that consists of two AEEA units, a γ-glutamate and 1,18-octadecanedioic acid. This lipophilic anchor makes the molecule attach to albumin. Furthermore, Lys 28 (34) has been substituted with Arg, to maintain the net charge and to simplify the derivatization at Lys 20. Together, these modifications increase the lifetime of Semaglutide dramatically: While GLP-1 has a half-life of just 2 minutes, the half-life of Semaglutide is about 7 days. Because of these smart innovations, the medication only needs to be injected once a week.

While during research and development, small amounts of Semaglutide have been produced by SPPS, the current industrial process is partially recombinant. First, most of the canonical backbone (amino acids 5-31) is made by recombinant expression in yeast, then the lipophilic albumin anchor is attached to the side chain of lysine 20. Finally, the Aib at the N-terminus is introduced, e.g., as His-Aib-Glu-Gly tetrapeptide, which avoids problems connected to aspartimide formation, compared to adding each of these amino acids separately. Other synthetic routes have been described, too (see references). 

Extending the serum half-life with these methods also is used in other injectable peptide drugs, e.g., Insulin Detemir (Levemir®) and Liraglutide (Victoza®). Lipophilic modification has also been used with siRNA, antisense oligonucleotides, antibodies and antibody fragments.

→ Interested in tools and building blocks to improve your peptide’s half-life? Browse our flyer “Peptide Modifiers”! Available Liraglutide, Semaglutide, and Tirzepatide building blocks are listed as well.

→ We are offering Liraglutide (LS-4050) and Semaglutide (LS-4040) as reference standard for peptide synthesis.

References: 

Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide; J. Lau, P. Bloch, L. Schäffer, I. Pettersson, J. Spetzler, J. Kofoed, K. Madsen, L. Bjerre Knudsen, J. McGuire, D. Bjerre Steensgaard, H. M. Strauss, D. X. Gram, S. Møller Knudsen, F. Seier Nielsen, P. Thygesen, S. Reedtz-Runge, T. Kruse; J. Med. Chem. 2015; 58(18): 7370-7380. https://doi.org/10.1021/acs.jmedchem.5b00726 

The Discovery and Development of Liraglutide and Semaglutide; L. B. Knudsen; J. Lau; Front Endocrinol (Lausanne) 2019; 10: 155. https://doi.org/10.3389/fendo.2019.00155

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art; M. A. Nauck, D. R. Quast, J. Wefers, J. J. Meier; Mol. Metab. 2021; 46: 101102. https://doi.org/10.1016/j.molmet.2020.101102 

Scalable and Sustainable DMF-Free Solid-Phase Synthesis of Liraglutide by 1-Tert-Butyl-3-Ethylcarbodiimide-Mediated Couplings and Catch-and-Release Acylation and Purification Strategies; L. Pacini, M. Kumar Muthyala, R. Zitterbart, O. Marder, P. Rovero, A. M. Papini; Int. J. Pept. Res. Ther. 2025; 3: article number 43. https://doi.org/10.1007/s10989-025-10703-4

Semi-recombinant preparation of GLP-1 analogs; J. Faergeman Lau, A. Sloth Andersen, P. Bloch, J. Lau, P. W. Garibay, T. Kruse, I. S. Nielsen Nørby, C. U. Jessen, C. Christensen, J. C. Norrild; 2007. US2010/0317057A1. https://patents.google.com/patent/US20100317057A1/ja 

Total Synthesis of Semaglutide Based on a Soluble Hydrophobic-Support-Assisted Liquid-Phase Synthetic Method; X. Liu, N. Zhang, X. Gu, Y. Qin, D. Song, L. Zhang, S. Ma; ACS Comb. Sci. 2020; 22(12): 821-825. https://doi.org/10.1021/acscombsci.0c00134 

Copper(II) Lysinate and Pseudoproline Assistance in the Convergent Synthesis of the GLP‑1 Receptor Agonists Liraglutide and Semaglutide; I. Guryanov, A. Orlandin, I. De Paola, A. Viola, B. Biondi, D. Badocco, F. Formaggio, A. Ricci, W. Cabri; Org. Proc. Res. Dev. 2021; 25(7): 1598-1611. https://doi.org/10.1021/acs.oprd.1c00021 

Albumin Binding as a General Strategy for Improving the Pharmacokinetics of Proteins; M. S. Dennis, M. Zhang, Y. G. Meng, M. Kadkhodayan, D. Kirchhofer, D. Combs, L. A. Damico; J. Biol. Chem. 2002; 277(38): 35035-35043. https://doi.org/10.1074/jbc.M205854200 

Mechanisms and optimization of in vivo delivery of lipophilic siRNAs; C. Wolfrum, S. Shi, K. N. Jayaprakash, M. Jayaraman, G. Wang, R. K. Pandey, K. G. Rajeev, T. Nakayama, K. Charrise, E. M. Ndungo, T. Zimmermann, V. Koteliansky, M. Manoharan, M. Stoffel; Nat. Biotechnol. 2007; 25(10): 1149-1157. https://doi.org/10.1038/nbt1339 

Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle; T. P. Prakash, A. E Mullick, R. G. Lee, J. Yu, S. T. Yeh, A. Low, A. E. Chappell, M. E. Østergaard, S. Murray, H. J. Gaus, E. E. Swayze, P. P. Seth; Nucleic Acids Res. 2019; 47(12): 6029-6044. https://doi.org/10.1093/nar/gkz354