The application of peptide-based active pharmaceutical ingredients is very promising due to their potential high target binding properties, their close relation to naturally occurring biomolecules, and their good biodegradability. However, the latter may also be a disadvantage, as peptides may be degraded, metabolized, or excreted very fast and thus require high or frequently repeated dosing. Therefore, methods were developed to keep those peptides longer in the patient’s body.

Looking at the most successful peptide APIs in the last years, we see that these analogues of Insulin, GLP1, or GIP use fatty acid-like attachments plus further modifications to extend their plasma half-life. The current market leader Semaglutide has already crossed the 10-billion-dollar threshold and its competitor Tirzepatide is on a promising path to doing the same.

Both are derived from peptide hormones with only minor sequence changes. Whereas the natural peptides have plasma half-lives of only a few minutes – which is much too short for an efficient pharmaceutical application – their modifications have enabled even once-per-week applications of the APIs.

As broadly known in the peptide community, this increasing of the half-life is achieved by introducing the branched, protease-resistant amino acid Aib, and by adding long fatty acid derivatives that allow the peptide to bind to albumin, thus preventing it from renal excretion.

Typical building blocks used in peptide APIs like Semaglutide, Tirzepatide, or Insulin Degludec.

If you should intend to develop biosimilars of Insulin Degludec, Liraglutide, Semaglutide, or Tirzepatide: Iris biotech can provide you with all potential building blocks, and we can also deliver potential impurities, for example with D-Lysine or D-Glutamine instead of the L-isomers or with fatty acids of different length. For further inspiration, please see our updated flyer “peptide modifiers” . If you cannot find a particular fatty amino acid building block, please send us your inquiry! We can supply fine-tuned solutions not only for half-life extension but for numerous other functions.

But honestly, we would prefer if you would aim to develop your own new API with completely new functionalities. Iris Biotech’s ambition is to provide you with exactly the best suitable building blocks.

References:

Pharmacotherapy for obesity: moving towards efficacy improvement; W. Coutinho, B. Halpern; Diabetology & Metabolic Syndrome 2024; 16: 6. https://doi.org/10.1186/s13098-023-01233-4

Drug Therapies for Diabetes; R. Weinberg Sibony, O. Segev, S. Dor, I. Raz; International Journal of Molecular Sciences 2023; 24: 17147. https://doi.org/10.3390/ijms242417147

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial; W. T. Garvey, J. P. Frias, et al.; The Lancet 2023; 402: 613-626. https://doi.org/10.1016/S0140-6736(23)01200-X

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.

The ABC of Insulin: The Organic Chemistry of a Small Protein; K. J. Jensen, M. Ostergaard, N. M. Kumar; Chemistry 2020; n/a. https://doi.org/10.1002/chem.202000337

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

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

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

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

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