Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)

Abstract

The innovative development of azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) has produced selective modulators of the cluster of differentiation 36 receptor (CD36). The azapeptide CD36 modulators curb macrophage-driven inflammation and mitigate atherosclerotic and angiogenic pathology. In macrophages activated with Toll-like receptor-2 heterodimer agonist, they reduced nitric oxide production and proinflammatory cytokine release. In a mouse choroidal explant microvascular sprouting model, they inhibited neovascularization. In murine models of cardiovascular injury, CD36-selective azapeptide modulators exhibited cardioprotective and anti-atherosclerotic effects. In subretinal inflammation models, they altered activated mononuclear phagocyte metabolism and decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury associated with retinitis pigmentosa, diabetic retinopathy and age-related macular degeneration. The translation of GHRP-6 to potent and selective linear and cyclic azapeptide modulators of CD36 is outlined in this review which highlights the relevance of turn geometry for activity and the biomedical potential of prototypes for the beneficial treatment of a wide range of cardiovascular, metabolic and immunological disorders.

The CD36 Ligand‐Promoted Autophagy Protects Retinal Pigment Epithelial Cells from Oxidative Stress

“…New approaches are urgently needed for preventing and halting the pathology of AMD ideally at the earlier stages. CD36 is a promising therapeutic target due in part to the involvement in sterile inflammation and lipid deposition observed in dry AMD [ 46 ]. Previously, GHRP-6 derivatives have demonstrated beneficial effects as CD36 ligands that preserve photoreceptors in mouse models of AMD [ 18 , 20 ].…”

N-Amino-imidazol-2-one (Nai) Residues as Tools for Peptide Mimicry: Synthesis, Conformational Analysis and Biomedical Applications

“…40 CD36 is implicated in a variety of biological processes including inflammation, angiogenesis, oxidized lipoprotein transport and autophagy. 43 In the pursuit of CD36 ligands for biomedical applications, growth-hormone-releasing peptide-6 (GHRP-6, H-His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 ) analogues have been pursued and shown to possess interesting modulatory activity but low selectivity. 44 In contrast, CD36 selectivity has been achieved by employing azapeptide GHRP-6 analogues.…”

“…43 Relatively high CD36 binding affinities, selectivity and promising utility have been exhibited by [azaPhe 4 ]-GHRP-6 analogues. [43][44][45] For example, [aza-Tyr 4 ]-GHRP-6 (46) has exhibited selective micromolar CD36 binding affinity and protective effects in models of macrophage-driven inflammation. 43 In raw macrophages that were activated with the Toll-like receptor (TLR)-2 agonist (R)-fibroblast-stimulating lipopeptide (R-FSL-1), azapeptide 46 reduced nitric oxide production and diminished proinflammatory cytokine levels.…”

“…[43][44][45] For example, [aza-Tyr 4 ]-GHRP-6 (46) has exhibited selective micromolar CD36 binding affinity and protective effects in models of macrophage-driven inflammation. 43 In raw macrophages that were activated with the Toll-like receptor (TLR)-2 agonist (R)-fibroblast-stimulating lipopeptide (R-FSL-1), azapeptide 46 reduced nitric oxide production and diminished proinflammatory cytokine levels. 45 5-Aryl Nai residues were introduced into [azaPhe 4 ]-GHRP-6 analogues using a solid-phase approach to study the biologically active backbone and side-chain topology of the azapeptide.…”

“…After removal of the Fmoc group, the sterically hindered and relatively non-nucleophilic semicarbazide was acylated using N-(Fmoc)alanyl chloride under microwave conditions. 46 Subsequent elongation of peptide resin 49 and purification by preparative high-performance Scheme 8 (5-Me)Nai almiramide peptide analogue synthesis 43 In comparison with the relatively high binding affinities (IC 50 ) of hexarelin (4.0 M) and [azaTyr 4 ]-GHRP-6 (46) (3.1 M), 5-aryl Nai analogues 50 and 51 engaged CD36 with approximately two-to three-fold lower binding affinity (8.1 and 10.0 M, respectively). 10 Furthermore, 5-aryl Nai peptides 50 and 51 demonstrated comparable abilities as [azaTyr 4 ]-GHRP-6 (46) in reducing nitric oxide production in macrophages stimulated with the TLR-2 agonist R-FSL-1.…”