Atheroprotective and atheroregressive potential of azapeptide derivatives of GHRP-6 as selective CD36 ligands in apolipoprotein E-deficient mice

Frégeau, Geneviève; Sarduy, Roger; Elimam, Hanan; Esposito, Cloé L.; Mellal, Katia; Ménard, Liliane; Graça, Silas D. Leitão da; Proulx, Caroline; Febbraio, Maria; Soto, Yosdel; Lubell, William D.; Ong, Huy; Marleau, Sylvie

doi:10.1016/j.atherosclerosis.2020.06.010

Cited by 5 publications

(16 citation statements)

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“…In the course of review, a publication in press was reported in which [aza-( N , N -diallylaminobut-2-ynyl)Gly 4 ]-GHRP-6 ( 49f ) was shown to diminish aortic lesion progression and reduce lesions in the aortic sinus of atherosclerotic mice below pre-existing levels [ 61 ]. Moreover, the effects of azapeptide 49f were associated with a relative increase of M2-like macrophages in lesions and reduced systemic inflammation [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…The role of adiponectin in sustaining the cardioprotective effect of azapeptide 15 after myocardial ischemia and reperfusion was further delineated by the annulation of restorative effects in the presence of an anti-adiponectin neutralizing antibody. In sum, treatment with [Ala 1 , azaPhe 4 ]-GHRP-6 (15) enhanced the cardioprotective effect of adiponectin in a CD36-dependent manner to prevent injury in induced murine models [60].Selective azapeptide CD36 ligands offer beneficial means for treating myocardial ischemia and reperfusion induced injury and related cardiometabolic and immunological disorders.In the course of review, a publication in press was reported in which [aza-(N,N-diallylaminobut-2-ynyl)Gly 4 ]-GHRP-6 (49f) was shown to diminish aortic lesion progression and reduce lesions in the aortic sinus of atherosclerotic mice below pre-existing levels[61]. Moreover, the effects of azapeptide 49f were associated with a relative increase of M2-like macrophages in lesions and reduced systemic inflammation[61].…”

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Azapeptide analogs of GHRP-6, MPE-003 ( Frégeau et al, 2020 ), and MPE-298 ( Supplementary Figure S1 ) were synthesized and characterized, as described previously ( Zhang et al, 2014 ; Ahsanullah et al, 2019 ), and reconstituted in sterile 0.9% NaCl before injection. MPE-003 was used as a positive control due to its well-characterized anti-atherosclerotic effect in apoE −/− mice ( Frégeau et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…Azapeptide analogs of GHRP-6, in which an amino amide is replaced by a semicarbazide, have demonstrated CD36 selectivity ( Proulx et al, 2012 ; Proulx et al, 2020 ). Notably, [aza-Tyr 4 ]- and [aza-( N , N -diallylaminobut-2-ynyl)Gly 4 ]-GHRP-6 (MPE-001 and MPE-003) were proven to be effective in reducing lesion progression, diminishing pro-inflammatory macrophage polarization, and lowering plasma inflammatory cytokines in a mouse model of atherosclerosis ( Frégeau et al, 2020 ). Cyclic azapeptides (e.g., MPE-298), which were prepared by A 3 -macrocyclization, were shown to display in vitro unprecedented CD36 binding affinity (IC 50 of 0.1 µM) ( Ohm et al, 2021 ), whereas linear azapeptides presented an IC 50 value of ∼1 µM ( Possi et al, 2017 ) and superior potency in reducing NO production and levels of major pro-inflammatory mediators (notably, CCL2 and IL-1) ( Zhang et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

A cyclic azapeptide ligand of the scavenger receptor CD36/SR-B2 reduces the atherosclerotic lesion progression and enhances plaque stability in apolipoprotein E-deficient mice

et al. 2023

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Atherosclerosis is a chronic inflammatory disease of the arterial walls that develops at predisposed sites. As a major risk factor for adverse cardiovascular pathology, atherosclerosis can progress to myocardial infarction and stroke, due to the rupture of unstable atherosclerotic lesions. Macrophage uptake of modified lipoproteins and metabolic dysfunction contributes significantly to the initiation and development of atherosclerotic lesions. The cluster of differentiation 36 receptor [CD36 (SR-B2)] plays a key role in atherosclerotic lesion progression and acts as an efferocytic molecule in the resolution of advanced plaque. In previous studies, linear azapeptide CD36 ligands were shown to exhibit anti-atherosclerotic properties. In the present study, a novel potent and selective macrocyclic azapeptide CD36 ligand, MPE-298, has proven effective in protecting against atherosclerosis progression. Features of greater plaque stability were observed after 8 weeks of daily injections with the cyclic azapeptide in apolipoprotein E-deficient mice fed a high-fat high-cholesterol diet.

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“…Azapeptides are synthetic molecules analogous to growth hormone-releasing peptide-6 (GHRP-6) that bind to the oxLDL binding site on CD36. MPE-001 and MPE-003 azapeptides are effective in reducing sinus and aortic arch lesions in a mouse model of atherosclerosis (high-fat high cholesterol fed ApoE −/− mice) ( Frégeau et al, 2020 ). However, their effects in cancer cells have not been studied.…”

Section: Strategies To Inhibit Cd36 Functionmentioning

confidence: 99%

Role of CD36 in cancer progression, stemness, and targeting

Guerrero-Rodriguez

Mata-Cruz

Pérez‐Tapia

et al. 2022

Front. Cell Dev. Biol.

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CD36 is highly expressed in diverse tumor types and its expression correlates with advanced stages, poor prognosis, and reduced survival. In cancer cells, CD36: 1) increases fatty acid uptake, reprogramming lipid metabolism; 2) favors cancer cell proliferation, and 3) promotes epithelial-mesenchymal transition. Furthermore, CD36 expression correlates with the expression of cancer stem cell markers and CD36+ cancer cells display increased stemness functional properties, including clonogenicity, chemo- and radioresistance, and metastasis-initiating capability, suggesting CD36 is a marker of the cancer stem cell population. Thus, CD36 has been pointed as a potential therapeutic target in cancer. At present, at least three different types of molecules have been developed for reducing CD36-mediated functions: blocking monoclonal antibodies, small-molecule inhibitors, and compounds that knock-down CD36 expression. Herein, we review the role of CD36 in cancer progression, its participation in stemness control, as well as the efficacy of reported CD36 inhibitors in cancer cell cultures and animal models. Overall, the evidence compiled points that CD36 is a valid target for the development of new anti-cancer therapies.

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Atheroprotective and atheroregressive potential of azapeptide derivatives of GHRP-6 as selective CD36 ligands in apolipoprotein E-deficient mice

Cited by 5 publications

References 48 publications

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

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

A cyclic azapeptide ligand of the scavenger receptor CD36/SR-B2 reduces the atherosclerotic lesion progression and enhances plaque stability in apolipoprotein E-deficient mice

Role of CD36 in cancer progression, stemness, and targeting

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