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.

Fatty acid acylated peptide therapeutics: discovery of omega-n oxidation of the lipid chain as a novel metabolic pathway in preclinical species / Esposito, Simone; Krick, Alain; Pasquier, Olivier; Bonche, Fabrice; Ingenito, Raffaele; Magotti, Paola; Bianchi, Elisabetta; Monteagudo, Edith; Gallo, Mariana; Cicero, Daniel Oscar; Orsatti, Laura; Veneziano, Maria; Caretti, Fulvia; Mele, Riccardo; Roversi, Daniela; Gennari, Nadia; Brasseur, Denis; Gauzy-Lazo, Laurence; Duclos, Olivier; Mauriac, Christine; Illiano, Stephane; Mallart, Sergio. - In: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS. - ISSN 0731-7085. - 227:(2023), p. 115256.115256. [10.1016/j.jpba.2023.115256]

Fatty acid acylated peptide therapeutics: discovery of omega-n oxidation of the lipid chain as a novel metabolic pathway in preclinical species

Gallo, Mariana
Investigation
;
2023-01-01

Abstract

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.
2023
Fatty acid acylated peptide therapeutics: discovery of omega-n oxidation of the lipid chain as a novel metabolic pathway in preclinical species / Esposito, Simone; Krick, Alain; Pasquier, Olivier; Bonche, Fabrice; Ingenito, Raffaele; Magotti, Paola; Bianchi, Elisabetta; Monteagudo, Edith; Gallo, Mariana; Cicero, Daniel Oscar; Orsatti, Laura; Veneziano, Maria; Caretti, Fulvia; Mele, Riccardo; Roversi, Daniela; Gennari, Nadia; Brasseur, Denis; Gauzy-Lazo, Laurence; Duclos, Olivier; Mauriac, Christine; Illiano, Stephane; Mallart, Sergio. - In: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS. - ISSN 0731-7085. - 227:(2023), p. 115256.115256. [10.1016/j.jpba.2023.115256]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2938235
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 1
social impact