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

Abstract

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.

A Review on Azapeptides: The Promising Peptidomimetics

“…[Aza Phe 4 ]-GHRP-6 Improved binding, selectivity and affinity to cluster of differentiation (CD36) scavenger receptor which is implicated in atherosclerosis, angiogenesis and age related macular degeneration [22] [19]…”

Peptide Coupling Challenges to Aza-Pipecolyl Smac Mimetic

“…Azopeptides have been employed in the synthesis of peptide analogs bearing semicarbazides as amino amide surrogates, so called azapeptides [2]. For example, the DielsAlder reaction of a diazine residue with cyclopentadiene provided aza-methano-pipecolyl peptide 5 (Scheme 1) [1].…”

Solid-Phase Synthesis of Azasulfurylphenylalanine4-GHRP-6

“…Solid-phase chemistry has however yet to be employed for the synthesis of azasulfurylpeptides. Targeting an azasulfurylpeptide analog of growth hormone releasing peptide-6 (GHRP-6, His-D-TrpAla-Trp-D-Phe-Lys-NH2) in the context of our program to develop modulators of the cluster of differentiation-36 [9][10][11], we report herein a solid-phase approach to prepare azasulfurylphenylalanine 4 [AsF 4 ]-GHRP-6.…”