Solid-phase peptide head-to-side chain cyclodimerization: Discovery of C2-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors

Alexander V. Mayorov, Minying Cai, Erin S. Palmer, Zhihua Liu, James P. Cain, Josef Vagner, Dev Trivedi, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

A novel hybrid melanocortin pharmacophore was designed based on the pharmacophores of the agouti-signaling protein (ASIP), an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. The designed hybrid ASIP/MSH pharmacophore was explored in monomeric cyclic, and cyclodimeric templates. The monomeric cyclic disulfide series yielded peptides with hMC3R-selective non-competitive binding affinities. The direct on-resin peptide lactam cyclodimerization yielded nanomolar range (25-120 nM) hMC1R-selective full and partial agonists in the cyclodimeric lactam series which demonstrates an improvement over the previous attempts at hybridization of MSH and agouti protein sequences. The secondary structure-oriented pharmacophore hybridization strategy will prove useful in development of unique allosteric and orthosteric melanocortin receptor modulators. This report also illustrates the utility of peptide cyclodimerization for the development of novel GPCR peptide ligands.

Original languageEnglish (US)
Pages (from-to)1894-1905
Number of pages12
JournalPeptides
Volume31
Issue number10
DOIs
StatePublished - Oct 1 2010

Keywords

  • Agouti-signaling protein
  • C -symmetry
  • Cyclodimerization
  • Macrocyclic peptide
  • Melanocortin receptors

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

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