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

被引：4

作者：

Esposito, Simone ^{[1
,10
]}

Krick, Alain ^{[2
]}

Pasquier, Olivier ^{[2
]}

Bonche, Fabrice ^{[2
]}

Ingenito, Raffaele ^{[3
,11
]}

Magotti, Paola ^{[3
,12
]}

Bianchi, Elisabetta ^{[3
]}

Monteagudo, Edith ^{[1
,4
,13
]}

Gallo, Mariana ^{[5
,14
]}

Cicero, Daniel Oscar ^{[6
]}

Orsatti, Laura ^{[4
]}

Veneziano, Maria ^{[4
]}

Caretti, Fulvia ^{[4
]}

Mele, Riccardo ^{[1
]}

Roversi, Daniela ^{[3
]}

Gennari, Nadia ^{[7
]}

Brasseur, Denis ^{[8
]}

Gauzy-Lazo, Laurence ^{[8
]}

Duclos, Olivier ^{[8
]}

Mauriac, Christine ^{[2
]}

Illiano, Stephane ^{[9
]}

Mallart, Sergio ^{[8
,15
]}

机构：

[1] IRBM Spa, Expt Pharmacol Dept, Biodistribut Biotransformat & Analyt Sci Unit, Via Pontina Km 30 600, I-00071 Rome, Italy

[2] DMPK France, Sanofi R&D, 1 rue Pierre Brossolette, F-91385 Chilly Mazarin, France

[3] IRBM Spa, Peptides & Small Mol R&D Dept, Peptide Chem Unit, Via Pontina Km 30 600, Rome, Italy

[4] IRBM Spa, Expt Pharmacol Dept, PK PD & Bioanalyt Unit, Via Pontina Km 30 600, I-00071 Rome, Italy

[5] IRBM Spa, Computat Chem & Struct Biol Dept, Struct Biol Unit, Via Pontina Km 30 600, I-00071 Rome, Italy

[6] Univ Roma Tor Vergata, Dept Chem Sci & Technol, I-00133 Rome, Italy

[7] IRBM Spa, Translat Res Dept, High Throughput Biol & Screening, Via Pontina Km 30 600, I-00071 Rome, Italy

[8] Sanofi R&D, Integrated Drug Discovery, 1 rue Pierre Brossolette, F-91385 Chilly Mazarin, France

[9] Sanofi R&D, Invest Toxicol, 1 rue Pierre Brossolette, F-91385 Chilly Mazarin, France

[10] Selvita SA, Michala Bobrzynskiego 14, PL-30348 Krakow, Poland

[11] Naturamla Srl, Via Monte Zebio 43, I-00195 Rome, Italy

[12] Zealand Pharm AS, Sydmarken 11, DK-2860 Soborg, Denmark

[13] CHDI Fdn, 6080 Ctr Dr, Suite 700, Los Angeles, CA 90045 USA

[14] Univ Parma, Dept Med & Surg, I-43126 Parma, Italy

[15] Inst Pasteur Paris, 28 rue Docteur Roux, F-75015 Paris, France

来源：

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS | 2023年 / 227卷

关键词：

Peptide drugs; Relaxin; Metabolism; LC-HRMS; NMR; Omega -n oxidation; HALF-LIFE EXTENSION; ANALOG; PROTRACTION; MECHANISM; EXCRETION; INSULIN;

D O I：

10.1016/j.jpba.2023.115256

中图分类号：

O65 [分析化学];

学科分类号：

070302 ; 081704 ;

摘要：

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 omega-1, omega-2 and omega-3 positions. Structuremetabolism 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.

引用

页数：12

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