1. Fatty acid acylated peptide therapeutics: discovery of omega-n oxidation of the lipid chain as a novel metabolic pathway in preclinical species
- Author
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Simone Esposito, Alain Krick, Olivier Pasquier, Fabrice Bonche, Raffaele Ingenito, Paola Magotti, Elisabetta Bianchi, Edith Monteagudo, Mariana Gallo, Daniel Oscar Cicero, Laura Orsatti, Maria Veneziano, Fulvia Caretti, Riccardo Mele, Daniela Roversi, Nadia Gennari, Denis Brasseur, Laurence Gauzy-Lazo, Olivier Duclos, Christine Mauriac, Stephane Illiano, Sergio Mallart, Sanofi Aventis R&D [Chilly-Mazarin], and Institut Pasteur [Paris] (IP)
- Subjects
peptide drugs ,LC-HRMS ,Metabolism ,Omega-n oxidation ,[SDV]Life Sciences [q-bio] ,Clinical Biochemistry ,Drug Discovery ,Relaxin ,Pharmaceutical Science ,Settore CHIM/08 - Chimica Farmaceutica ,Spectroscopy ,NMR ,Analytical Chemistry - Abstract
International audience; We recently described C18 fatty acid acylated peptides as a new class of potent long-lasting single-chain RXFP1 agonists that displayed relaxin-like activities in vivo. Early pharmacokinetics and toxicological studies of these stearic acid acylated peptides revealed a relevant oxidative metabolism occurring in dog and minipig, and also seen at a lower extent in monkey and rat. Mass spectrometry combined to NMR spectroscopy studies revealed that the oxidation occurred, unexpectedly, on the stearic acid chain at ω-1, ω-2 and ω-3 positions. Structure-metabolism relationship studies on acylated analogues with different fatty acids lengths (C15-C20) showed that the extent of oxidation was higher with longer chains. The oxidized metabolites could be generated in vitro using liver microsomes and engineered bacterial CYPs. These systems were correlating poorly with in vivo metabolism observed across species; however, the results suggest that this biotransformation pathway might be catalyzed by some unknown CYP enzymes.
- Published
- 2023