Aza-scanning of the potent melanocortin receptor agonist Ac-His-D-Phe-Arg-Trp-NH.
The melanocortin pathway is an important participant in the regulation of skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. Melanocortin agonists contain the putative sequence 'His-Phe-Arg-Trp', which has been designated as the 'message' sequence for melanocortin peptides, and this sequence has been hypothesized to adopt a bioactive reverse turn conformation. Exploring the relationship between its structure and biological activity, we report the synthesis and evaluation of seven aza-analogs of the potent melanocortin receptor agonist Ac-His-D-Phe-Arg-Trp-NH2. Aza-amino acids, in which the alpha-carbon was replaced by nitrogen, were inserted along the peptide sequence to probe the importance of local configuration and turn conformation on the biology of this tetrapeptide. Although systematic substitution of aza-amino acids for the D-Phe and Arg residues led to a significant loss of activity relative to the parent peptide for all melanocortin receptor subtypes examined, substitution of aza-amino acids at the C-terminal Trp residue gave analogs equipotent to the parent peptide. In summary, the aza-scan has demonstrated that recognition of this tetrapeptide by the melanocortin receptors is particularly sensitive to modifications of configuration and conformation at the D-Phe and Arg residues versus the Trp amino acid. In light of aza-residues imparting resistance from enzymatic degradation, C-terminal aza-amino acid analogs may be used to design new peptide mimics with enhanced metabolic stability.
Boeglin
D
D
Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada.
Xiang
Z
Z
Sorenson
N B
NB
Wood
M S
MS
Haskell-Luevano
C
C
Lubell
W D
WD
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D001372:Aza Compounds; D009842:Oligopeptides; D010456:Peptides, Cyclic; D044102:Receptor, Melanocortin, Type 1; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C459203:acetyl-histidyl-phenylalanyl-arginyl-tryptophanamide; C086971:melanocortin 5 receptor