Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity

Carrie Haskell-Luevano, Tomi K. Sawyer, Siska Hendrata, Cheryl North, Laila Panahinia, Martha Stum, Douglas J. Staples, Anna M. De Lauro Castrucci, Mac E. Hadley, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Systematic analysis of fragment derivatives of the superpotent α-MSH analogue, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) 'active site.' The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereochemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His6 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

Original languageEnglish (US)
Pages (from-to)995-1002
Number of pages8
JournalPeptides
Volume17
Issue number6
DOIs
StatePublished - 1996

Bibliographical note

Funding Information:
This work was supported by grants from the U.S. Public Health Service, DK 17420 (V.J.H.) and DK0923 1 (C.H.L.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the USPHS.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • Ac-[Nle,DPhe]α-MSH
  • NDP-MSH
  • melanotrop in pharmacophore
  • melanotropin
  • α-MSH
  • α-melanocyte stimulating hormone

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