On-line synthesis of pseudopeptide library incorporating a benzodiazepinone turn mimic: biological evaluation on MC1 receptors.
Alpha melanocyte stimulating hormone (alpha-MSH) is a widely distributed hormone. This tridecapeptide exhibits various biological activities mediated through different receptors. alpha-MSH binds to the melanocortin-1 receptor (MC1-R), mainly expressed in keratinocytes and melanocytes, inducing melanogenesis and anti-inflammatory processes. The central His-Phe-Arg-Trp tetrapeptide sequence of alpha-MSH is known to form a turn in the bioactive conformation. To find new potent analogs of alpha-MSH, we decided to introduce non-peptide building blocks in the alpha-MSH sequence. Molecular modeling studies showed that two amino acids of the central core sequence could be replaced by the benzodiazepinone building block without loosing the beta-turn conformation. Benzodiazepines are well-known pharmacophores exhibiting a wide scope of biological activities and are described as constrained dipeptide mimics templates. Although numerous synthetic pathways leading to benzodiazepinones have been described in literature, no methodology has 1,4-benzodiazepine-2,5-diones building blocks bearing a free carboxylic acid function and a protected amino function suitable for incorporation into peptide sequences. In this study, we report the synthesis of peptides with a benzodiazepinone moiety obtained directly during the course of solid-phase peptide synthesis (SPPS). This "on-line" strategy leads to the generation of a 54-member pseudo-peptide library of alpha-MSH analogs. After LC/MS purification, binding assays were performed on the MC1 receptor leading to the discovery of several micromolar ligands.
Verdié
Pascal
P
Laboratoire des Aminoacides, Peptides et Protéines (LAPP), UMR 5810, Faculté de Pharmacie, Université de Montpellier I et II, 15 avenue Charles Flahault, 34060 Montpellier, France.
Subra
Gilles
G
Feliu
Lidia
L
Sanchez
Pierre
P
Bergé
Gilbert
G
Garcin
Geneviève
G
Martinez
Jean
J
D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis*; D044102:Receptor, Melanocortin, Type 1 / Q000187:drug effects*
D001570:Benzodiazepinones; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1