Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators

Fernandez, Kleinberg X.; Fischer, Conrad; Vu, Jennie; Gheblawi, Mahmoud; Wang, Wang; Gottschalk, Samantha; Iturrioz, Xavier; Llorens‐Cortés, Catherine; Oudit, Gavin Y.; Vederas, John C.

doi:10.1039/d1md00120e

Cited by 11 publications

(11 citation statements)

References 48 publications

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“…It was reported that apelin-13 can decrease blood pressure (BP) and increase heart rate (HR) [ 28 , 29 , 30 , 31 , 32 , 33 ] ( Figure 2 ).…”

Section: Cardiovascular Effects Of Apelinsmentioning

confidence: 99%

“…Therefore, the long-term cardioprotective effect of a chronic daily single administration of elabela-32, apelin-13, and Pyr1-apelin-13 in animals with MI or pressure overload is surprising [ 55 , 58 , 60 , 62 , 66 ]. The duration of the hypotensive effect of apelin-13 and apelin-17 analogues to remain stable during enzymatic hydrolysis before reducing BP in mice was about 60 min [ 33 ]. It is quite obvious that apelins that remain stable during enzymatic hydrolysis with a long half-life have the greatest prospects for clinical use in the treatment of stroke, acute myocardial infarction, and in the prevention of adverse myocardial remodeling.…”

Section: The Synthetic Analogues Of Apelinsmentioning

confidence: 99%

“…Tran et al synthesized apelin-13 analogues with an in vivo half-life of 3.7 h [ 92 ]. Further reports have been conducted on synthesizing apelin-13 analogues with a plasma half-life of 3–8 h [ 33 ].…”

Section: The Synthetic Analogues Of Apelinsmentioning

confidence: 99%

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Apelin Is a Prototype of Novel Drugs for the Treatment of Acute Myocardial Infarction and Adverse Myocardial Remodeling

et al. 2023

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In-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is 5–6%. Consequently, it is necessary to develop fundamentally novel drugs capable of reducing mortality in patients with acute myocardial infarction. Apelins could be the prototype for such drugs. Chronic administration of apelins mitigates adverse myocardial remodeling in animals with myocardial infarction or pressure overload. The cardioprotective effect of apelins is accompanied by blockage of the MPT pore, GSK-3β, and the activation of PI3-kinase, Akt, ERK1/2, NO-synthase, superoxide dismutase, glutathione peroxidase, matrix metalloproteinase, the epidermal growth factor receptor, Src kinase, the mitoKATP channel, guanylyl cyclase, phospholipase C, protein kinase C, the Na+/H+ exchanger, and the Na+/Ca2+ exchanger. The cardioprotective effect of apelins is associated with the inhibition of apoptosis and ferroptosis. Apelins stimulate the autophagy of cardiomyocytes. Synthetic apelin analogues are prospective compounds for the development of novel cardioprotective drugs.

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“…It was reported that apelin-13 can decrease blood pressure (BP) and increase heart rate (HR) [ 28 , 29 , 30 , 31 , 32 , 33 ] ( Figure 2 ).…”

Section: Cardiovascular Effects Of Apelinsmentioning

confidence: 99%

Section: The Synthetic Analogues Of Apelinsmentioning

confidence: 99%

See 1 more Smart Citation

Apelin Is a Prototype of Novel Drugs for the Treatment of Acute Myocardial Infarction and Adverse Myocardial Remodeling

et al. 2023

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“…The system is a suitable pharmacological target: recent discoveries of novel synthetic Apelin-receptor ligands with increased half/life (LIT01-196, l-homoarginine aks l-hArg, and non-canonical amino acids l-cyclohexylalanine aka l-Cha, etc.) and antagonists have paved the way towards clinical trials [ 8 , 9 , 10 ]. For a comprehensive review of the newly synthesized APLNR ligands, refer to Fischer et al [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain

Ivanov

Stoyanov

Pavlov

et al. 2022

Genes

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Apelin, a peptide initially isolated from bovine stomach extract, is an endogenous ligand for the Apelin Receptor (APLNR). Subsequently, a second peptide, ELABELA, that can bind to the receptor has been identified. The Apelin receptor and its endogenous ligands are widely distributed in mammalian organs. A growing body of evidence suggests that this system participates in various signaling cascades that can regulate cell proliferation, blood pressure, fluid homeostasis, feeding behavior, and pituitary hormone release. Additional research has been done to elucidate the system’s potential role in neurogenesis, the pathophysiology of Glioblastoma multiforme, and the protective effects of apelin peptides on some neurological and psychiatric disorders-ischemic stroke, epilepsy, Parkinson’s, and Alzheimer’s disease. This review discusses the current knowledge on the apelinergic system’s involvement in brain physiology in health and disease.

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“…Recently, Vederas’ group has worked on modifications of the NEP cleavage site. They obtained agonists with good affinity and stability, but without studying the potential for signaling bias . In addition, many efforts have been made in recent years to develop small molecule agonists of the APJ receptor. ,− Nevertheless, the development of peptide analogues allows an easy and rapid approach for structure–activity relationship (SAR) studies and functional selectivity, which is still poorly understood.…”

mentioning

confidence: 99%

Signaling Modulation via Minimal C-Terminal Modifications of Apelin-13

Théroux

Hauwe

Tran

et al. 2023

ACS Pharmacol. Transl. Sci.

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Apelin is an endogenous peptide that is involved in many diseases such as cardiovascular diseases, obesity, and cancer, which has made it an attractive target for drug discovery. Herein, we explore the penultimate and final sequence positions of [Pyr1]-apelin-13 (Ape13) via C-terminal N α-alkylated amide bonds and the introduction of positive charges, potentially targeting the allosteric sodium pocket, by assessing the binding affinity and signaling profiles at the apelin receptor (APJ). Synthetic analogues modified within this segment of Ape13 showed high affinity (K i 0.12–0.17 nM vs Ape13 K i 0.7 nM), potent Gαi1 activation (EC50 Gαi1 0.4–0.9 nM vs Ape13 EC50 1.1 nM), partial agonist behavior disfavoring β-arrestin 2 recruitment for positively charged ligands (e.g., 49 (SBL-AP-058), EC50 β-arr2 275 nM, E max 54%) and high plasma stability for N-alkyl ligands (t 1/2 > 7 h vs Ape13 t 1/2 0.5 h). Combining the benefits of the N α-alkylated amide bond with the guanidino substitution in a constrained ligand led to 63 (SBL-AP-049), which displayed increased plasma stability (t 1/2 5.3 h) and strong reduction of β-arrestin 2 signaling with partial maximal efficacy (EC50 β-arr 864 nM, E max 48%), significantly reducing the hypotensive effect in vivo.

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Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators

Abstract: Cyclohexylalanine- and homoarginine-substituted apelin analogues are demonstrated to be metabolically stable APJR agonistic peptides with hypotensive effect.

Cited by 11 publications

References 48 publications

Apelin Is a Prototype of Novel Drugs for the Treatment of Acute Myocardial Infarction and Adverse Myocardial Remodeling

Apelin Is a Prototype of Novel Drugs for the Treatment of Acute Myocardial Infarction and Adverse Myocardial Remodeling

Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain

Signaling Modulation via Minimal C-Terminal Modifications of Apelin-13

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