Discovery and structure-function analysis of alpha-melanocyte-stimulating hormone antagonists.
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.
Department of Internal Medicine, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-0812.
C K
CK
Jayawickreme
J M
JM
Quillan
G F
GF
Graminski
M R
MR
Lerner
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D000521:alpha-MSH / Q000037:antagonists & inhibitors*
D010455:Peptides; D000521:alpha-MSH