title: Chimeric NDP-MSH and MTII melanocortin peptides with agouti-related protein (AGRP) Arg-Phe-Phe amino acids possess agonist melanocortin receptor activity.
abstract: Agouti-related protein (AGRP) is one of only two known endogenous antagonists of G-protein coupled receptors (GPCRs). Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis, regulation of feeding behavior, and obesity. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these receptors. It has been hypothesized that the Arg-Phe-Phe (111-113) human AGRP amino acids may be mimicking the melanocortin agonist Phe-Arg-Trp (7-9) residue interactions with the melanocortin receptors that are important for both receptor molecular recognition and stimulation. To test this hypothesis, we generated thirteen chimeric peptide ligands based upon the melanocortin agonist peptides NDP-MSH (Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). In these chimeric ligands, the agonist DPhe-Arg-Trp amino acids were replaced by the AGRP Arg-Phe-Phe residues, and resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs), supporting the hypothesis that the AGRP antagonist ligand Arg-Phe-Phe residues mimic the agonist Phe-Arg-Trp amino acids. Interestingly, the Ac-Ser-Tyr-Ser-Nle4-Glu-His-Arg-DPhe-Phe-Gly-Lys-Pro-Val-NH2 peptide possessed 7 nM mMC1R agonist potency, and is 850-fold selective for the mMC1R versus the mMC3R, 2300-fold selective for the mMC1R versus the mMC4R, and 60-fold selective for the MC1R versus the mMC5R, resulting in the discovery of a new peptide template for the design of melanocortin receptor selective ligands.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, PO Box 100485, Gainesville, FL 32610-0485, USA.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Joseph
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wilczynski
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Holder
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.forename: Rayna M
authors.initials: RM
authors.lastname: Bauzo
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Scott
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D054369:Agouti-Related Protein; D000596:Amino Acids / Q000737:chemistry; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology*; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: C515198:AGRP protein, human; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D000596:Amino Acids; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011506:Proteins; D044101:Receptors, Melanocortin; D011993:Recombinant Fusion Proteins; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D000242:Cyclic AMP