Aza-scanning of the potent melanocortin receptor agonist Ac-His-D-Phe-Arg-Trp-NH

Chemical Biology & Drug Design
Damien BoeglinW D Lubell

Abstract

The melanocortin pathway is an important participant in the regulation of skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. Melanocortin agonists contain the putative sequence 'His-Phe-Arg-Trp', which has been designated as the 'message' sequence for melanocortin peptides, and this sequence has been hypothesized to adopt a bioactive reverse turn conformation. Exploring the relationship between its structure and biological activity, we report the synthesis and evaluation of seven aza-analogs of the potent melanocortin receptor agonist Ac-His-D-Phe-Arg-Trp-NH2. Aza-amino acids, in which the alpha-carbon was replaced by nitrogen, were inserted along the peptide sequence to probe the importance of local configuration and turn conformation on the biology of this tetrapeptide. Although systematic substitution of aza-amino acids for the D-Phe and Arg residues led to a significant loss of activity relative to the parent peptide for all melanocortin receptor subtypes examined, substitution of aza-amino acids at the C-terminal Trp residue gave analogs equipotent to the parent peptide. In summary, the aza-scan has demonstrated that recognition of this tetrapeptide by the melanocortin receptors i...Continue Reading

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Citations

Aug 3, 2011·Future Medicinal Chemistry·Caroline ProulxWilliam D Lubell
Nov 30, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Samir H Bouayad-Gervais, William D Lubell
Dec 21, 2012·Chemical Biology & Drug Design·Andrew G JamiesonWilliam D Lubell
Nov 18, 2014·Journal of Peptide Science : an Official Publication of the European Peptide Society·Ngoc-Duc DoanWilliam D Lubell
May 16, 2012·The Journal of Organic Chemistry·Jochen SpiegelWilliam D Lubell
Feb 5, 2013·The Journal of Organic Chemistry·Nader E Abo-DyaAlan R Katritzky
Jul 26, 2013·The Journal of Organic Chemistry·Suvendu BiswasAlan R Katritzky
Mar 15, 2014·Chemical Society Reviews·Ilker AvanAlan R Katritzky
Jun 10, 2017·Accounts of Chemical Research·Ramesh ChingleWilliam D Lubell

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