Synthesis and in vitro study of a diglyceride prodrug of a peptide.
A diglyceride derivative of a pentapeptide renin inhibitor, the 1,3-dipalmitoyl-[Iva-Phe-Nle-Sta-Ala-Sta-acetyl]-glycerol was synthesized and tested in vitro as a potential prodrug for oral administration. The ability of the diglyceride analog to inhibit the renin activity was equivalent to that of the parent peptide after predigestion with pancreatic lipase. Furthermore, the presence of the palmitoyl groups was found to induce, in vitro, an efficient protection of the peptide from gastric and intestinal hydrolysis. During incubation with intestinal and gastric fluids, and with alpha-chymotrypsin and pancreatic lipase, the glycerolipidic derivative was more stable than the peptide alone. These results support the use of glycerolipidic prodrug for oral administration of peptides.
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, URA CNRS 1218, Faculté de Pharmacie, Catenay-Malabry, France.
F
F
Delie
P
P
Couvreur
D
D
Nisato
J B
JB
Michel
F
F
Puisieux
Y
Y
Letourneux
D000595:Amino Acid Sequence; D002021:Buffers; D002586:Cesium; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004075:Diglycerides / Q000138:chemical synthesis*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008049:Lipase; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis*; D010455:Peptides / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis*; D012995:Solubility; D000092502:Renin Inhibitors
D002021:Buffers; D002586:Cesium; D004075:Diglycerides; D008049:Lipase; D009842:Oligopeptides; D010455:Peptides; D011355:Prodrugs; D000092502:Renin Inhibitors; C046599:SR 42128