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

J Med Chem. 2011 Mar 10;54(5):1379-90. doi: 10.1021/jm101425m. Epub 2011 Feb 9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Agouti-Related Protein / chemistry*
  • Amino Acid Sequence
  • Animals
  • HEK293 Cells
  • Heterocyclic Compounds, 1-Ring / chemical synthesis*
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacology
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Melanocortins / chemistry*
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology
  • Protein Structure, Secondary
  • Receptors, Melanocortin / agonists*
  • Receptors, Melanocortin / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis
  • Sulfides / chemistry
  • Sulfides / pharmacology

Substances

  • Agouti-Related Protein
  • Heterocyclic Compounds, 1-Ring
  • Ligands
  • Melanocortins
  • Oligopeptides
  • Peptide Fragments
  • Peptides, Cyclic
  • Peptidomimetics
  • Receptors, Melanocortin
  • Sulfides