Peptides represent a powerful class of drugs due to their low toxicity, good tolerability, high selectivity and high potency. The journey of peptide-based drugs started with the first use of the peptide insulin to treat diabetes in 1922. As mentioned in our newsletter on fatty acid building blocks, the activity of a peptide drug might be limited due to degradation by proteases. However, it is reported that the introduction of fatty acid-derivatized amino acids may increase the stability and plasma half-life of a peptide drug and thus improve its overall performance and activity.

Herein, we present the two marketed modified peptide blockbusters Liraglutide and Semaglutide. Liraglutide, sold under the brand names Victoza® and Saxenda®, and Semaglutide, sold under the brand names Ozempic® and Rybelsus®, are both anti-diabetic medications used to treat type 2 diabetes, obesity, and weight management. Both are long-acting analogs of the linear glucagon-like peptide-1 (GLP-1) modified with a fatty acid side chain to be more stable against metabolic degradation by peptidases. Thereby, the fatty acid enables the peptide to bind to albumin and thus being released from the serum protein at a slow, consistent rate enabling longer presence of the drug in blood circulation. Besides, the binding also results in slower degradation and reduced renal elimination compared to native GLP-1(7-37).

Amino Acid Sequences of GLP-1(7-37), Liraglutide, and Semaglutide.

Semaglutide was developed in 2012 by Novo Nordisk as a longer-acting alternative to Liraglutide. Whereas Liraglutide is approved for once-daily treatment, Semaglutide only requires weekly administration.

Iris Biotech offers the building blocks for manufacturing Liraglutide and Semaglutide, available in large scale and including documentation for GMP manufacturing of the peptide APIs (see related products). Besides, our portfolio also includes common impurities observed during the synthesis of both peptide drugs.

➔ Interested in the purification of Liraglutide using the Peptide Easy Clean (PEC) Technology? Check out our publication in Chimica Oggi and/or watch the recording of our last online workshop.

References:

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.

Synthetic peptide API manufacturing: A mini review of current perspectives for peptide manufacturing; J. H. Rasmussen; Bioorg. Med. Chem. 2018; 26(10): 2914-2918. https://doi.org/10.1016/j.bmc.2018.01.018.

Easy access to purified complex peptides on larger scales with the peptide easy clean technology – a liraglutide case study; N. Berger, M. Kumar Muthyala, D. Sarma, K. Rustler, T. Bruckdorfer, R. Zitterbart; Chimica Oggi 2021; 39(6): 38-41.

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. B. Knudsen, J. McGuire, D. B. Steensgaard, H. M. Strauss, D. X. Gram, S. M. Knudsen, F. S. Nielsen, P. Thygesen, S. Reedtz-Runge, T. Kruse; J. Med. Chem. 2015; 58(18): 7370-7380. https://doi.org/10.1021/acs.jmedchem.5b00726.

Peptide Half-Life Extension: Divalent, Small-Molecule Albumin Interactions Direct the Systemic Properties of Glucagon-Like Peptide-1 (GLP-1) Analogues; E. M. Bech, M. C. Martos-Maldonado, P. Wismann, K. K. Sørensen, S. B. van Witteloostuijn, M. B. Thygesen, N. Vrang, J. Jelsing, S. L. Pedersen, K. J. Jensen; J. Med. Chem. 2017; 60(17): 7434-7446. https://doi.org/10.1021/acs.jmedchem.7b00787.

Liraglutide for the treatment of type 2 diabetes; D. Shyangdan, E. Cummins, P. Royle, N. Waugh; Health Technol Assess 2011; 15(Suppl 1 Article 9). https://doi.org/10.3310/hta15Suppl1-09.

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates; C. F. Gotfredsen, A.-M. Mølck, I. Thorup, N. C. B. Nyborg, Z. Salanti, L. B. Knudsen, M. O. Larsen; Diabetes 2014; 63: 2486-2497. https://doi.org/10.2337/db13-1087.