Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a.
The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the D-Trp(2), Ala(3), or Trp(4) position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the D-Trp(2) residue proved important for CD36 receptor affinity; however, His(1) could be replaced by Ala(1) without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr(4)]-GHRP-6 (15), [Ala(1), azaPhe(2)]-GHRP-6 (16), and [azaLeu(3), Ala(6)]-GHRP-6 (33) all exhibited antiangiogenic activity.
Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada.
Caroline
C
Proulx
Émilie
É
Picard
Damien
D
Boeglin
Petra
P
Pohankova
Sylvain
S
Chemtob
Huy
H
Ong
William D
WD
Lubell
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D018955:CD36 Antigens / Q000378:metabolism*; D002460:Cell Line; D020128:Inhibitory Concentration 50; D008024:Ligands; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D054440:Receptors, Ghrelin / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D001372:Aza Compounds; D018955:CD36 Antigens; D008024:Ligands; D009842:Oligopeptides; D054440:Receptors, Ghrelin; C041048:growth hormone releasing hexapeptide