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

Anamika Singh, Andrzej Wilczynski, Jerry R. Holder, Rachel M. Witek, Marvin L. Dirain, Zhimin Xiang, Arthur S. Edison, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 1H 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.

Original languageEnglish (US)
Pages (from-to)1379-1390
Number of pages12
JournalJournal of medicinal chemistry
Volume54
Issue number5
DOIs
StatePublished - Mar 10 2011

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