title: Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR.
abstract: By use of a solid-phase synthetic approach, a bioactive reverse turn heterocycle was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein-coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nanomolar potency. Biophysical structural analysis [2D (1)H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families compared to the reference peptide and result in a novel template for further structure-function studies.
authors.affiliation: Department of Pharmacodynamics, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Anamika
authors.initials: A
authors.lastname: Singh
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wilczynski
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Holder
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Witek
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Dirain
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Edison
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D054369:Agouti-Related Protein / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D057809:HEK293 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D053486:Melanocortins / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054369:Agouti-Related Protein; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D053486:Melanocortins; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D044101:Receptors, Melanocortin; D013440:Sulfides