1. Academic Validation
  2. Discovery and structure-function analysis of alpha-melanocyte-stimulating hormone antagonists

Discovery and structure-function analysis of alpha-melanocyte-stimulating hormone antagonists

  • J Biol Chem. 1994 Nov 25;269(47):29846-54.
C K Jayawickreme 1 J M Quillan G F Graminski M R Lerner
Affiliations

Affiliation

  • 1 Department of Internal Medicine, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-0812.
PMID: 7961978
Abstract

Structure-function relationships of alpha-melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin) were investigated and novel alpha-MSH receptor antagonists were identified. Based on the alpha-MSH-[5-13] peptide sequence, a multi-use peptide library consisting of 31,360 structurally different candidates was generated, and approximately 40% of the Peptides were individually screened for their ability to block receptor function. This led to the identification of antagonists with a range of potencies and revealed structural requirements necessary for receptor inactivation. The most potent antagonist Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Pro-Val-NH2 has an IC50 value of 11 +/- 7 nM. Analysis revealed that D-Trp5 and Phe6 were crucial to its antagonistic properties which could be potentiated by D-Phe3. This study demonstrates that residues in positions 5-6, 7-9, and 10 of the alpha-MSH sequence constitute crucial determinants for potent antagonist activity.

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