Parallel synthesis of a lipopeptide library by hydrazone-based chemical ligation.
alpha-Melanocyte-stimulating hormone (alpha-MSH) is an endogeneous linear tridecapeptide with potential application for the modulation of skin tanning. To evaluate the interest of introducing a lipid moiety onto this peptide, we developed an efficient chemoselective parallel method to prepare a large series of analogues of alpha-melanocortin with high purity, varying the nature or the relative position of the lipid moiety. Two sets of building blocks containing lipidic alpha-oxo-aldehydes or alpha-hydrazinoacetyl peptides were combined to obtain a 102-membered library of amphiphilic alpha-MSH analogues. This library was pharmacologically tested at 1 x 10(-7) M for the ability to induce AMPc production in M4Be melanoma cell line after stimulation of the human melanocortin MC1 receptor. Among theses lipopeptides, 84 compounds exhibited an AMPc induction higher than Melitane, a patented alpha-MSH agonist. These results provide strong evidence of the interest of introduction of a lipid tail for the pharmacomodulation of bioactive peptides.
Dubs
Pascaline
P
Institut des Biomolécules Max Mousseron, Universités de Montpellier I et II, UMR-CNRS 5247, Faculté de Pharmacie, 34093 Montpellier, France.
Bourel-Bonnet
Line
L
Subra
Gilles
G
Blanpain
Annick
A
Melnyk
Oleg
O
Pinel
Anne-Marie
AM
Gras-Masse
Hélène
H
Martinez
Jean
J
D000447:Aldehydes / Q000138:chemical synthesis; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor / Q000187:drug effects; D002853:Chromatography, Liquid; D004586:Electrophoresis; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D008074:Lipoproteins / Q000138:chemical synthesis* / Q000494:pharmacology; D013058:Mass Spectrometry; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D000521:alpha-MSH / Q000737:chemistry* / Q000494:pharmacology
D000447:Aldehydes; D006835:Hydrazones; D008074:Lipoproteins; D019151:Peptide Library; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH