Fatty Di-Acids

Published on 02/05/2023

Peptide therapeutics – fewer injections/lower doses by prolonging their half-life via addition of a lipid modification that promotes binding to serum proteins such as albumin. Read on for recent innovations!

Due to their natural origin, peptide drugs often suffer from degradation by proteases, limiting their effectiveness as therapeutics. In this regard, lipidated amino acid building blocks have gained increasing interest for peptide engineering as their fatty acid alkyl chain promotes non-covalent binding to serum albumin, thereby improving the pharmacokinetic and pharmacologic properties of peptide APIs. With this strategy, long half-lives for otherwise unstable peptide APIs can be achieved, and the frequency and dosage of drug administration can typically be reduced.

The most prominent examples in this context are the marketed glucagon-like peptide-1 analog blockbuster drugs Liraglutide and Semaglutide.

In this regard, at Iris Biotech, we offer functionalized fatty di-acid derivatives as well as protected fatty di-acid modified amino acids. Thereby, the impact on half-life extension of the peptidic drug is depending on the type of modification, e.g., position of the attached fatty acid and the length of its alkyl chain. In a direct comparison, fatty di-acids typically outperform their monoacid counterparts.

Our latest portfolio additions are Fmoc-L-Lys(tBuO-Thap)-OH (FAA8990) and Fmoc-L-Lys(tBuO-Thap-L-Glu-OtBu)-OH (FAA8980).

Fig. 1: Structure of Fmoc-L-Lys(tBuO-Thap)-OH (FAA8990).

Fig. 2: Structure of Fmoc-L-Lys(tBuO-Thap-L-Glu-OtBu)-OH (FAA8980).

While FAA8990 has a C16:0 di-acid side chain with a terminal carboxyl group (hexadecanedioic acid/thapsic acid), FAA8980 has a second carboxyl group derived from an additional glutamic acid spacer. For synthetic convenience, the side chain carboxyl groups are orthogonally protected with OtBu, which can be removed as soon as the synthesis is completed.

See all our fatty acid building blocks available in our webshop or download our flyer peptide modifiers
You are interested in further technologies to increase your peptide’s stability during circulation? Discover our b,b-dimethylated amino acids, hydrolysis stable analogs, and polymers for drug delivery

References:
Synthesis of Lipidated Peptides; F. Rosi, G. Triola; Peptide Synthesis and Applications 2013; 161-189. https://doi.org/10.1007/978-1-62703-544-6_12

Synthetic lipidation of peptides and amino acids: monolayer structure and properties; P. Berndt, G. B. Fields, M. Tirrell; J. Am. Chem. Soc. 1995; 117: 9515-9522. https://doi.org/10.1021/ja00142a019

Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics; R. Kowalczyk, P. W. R. Harris, G. M. Williams, S.-H. Yang, M. A. Brimble; Peptides and Peptide-based Biomaterials and their Biomedical Applications 2017; 1030: 185-227. https://doi.org/10.1007/978-3-319-66095-0_9

Solid-Phase Synthesis of Lipidated Peptides; G. Kragol, M. Lumbierres, J. M. Palomo; H. Waldmann; Angew. Chem. Int. Ed. 2004; 116: 5963-5966. https://doi.org/10.1002/ange.200461150

Derivatization with fatty acids in peptide and protein drug discovery; P. Kurtzhals, S. Østergaard, E. Nishimura, T. Kjeldsen; Nat. Rev. 2023; 22: 59-80. https://doi.org/10.1038/s41573-022-00529-w

The effect of fatty diacid acylation of human PYY_3-36 on Y₂ receptor potency and half-life in minipigs S. Østergaard, J. F. Paulsson, J. Kofoed, F. Zosel, J. Olsen, C. Bekker Jeppesen, J. Spetzler, L. Ynddal, L. Gram Schleiss, B. Østergaard Christoffersen, K. Raun, U. Sensfuss, F. S. Nielsen, R. Jørgensen, B. S. Wulff; Scientific Reports 2021; 11: 21179. https://doi.org/10.1038/s41598-021-00654-3