A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects

Tran, Kien Trung; Murza, Alexandre; Sainsily, Xavier; Coquerel, David; Côté, Jérôme; Belleville, Karine; Haroune, Lounès; Longpré, Jean‐Michel; Dumaine, Robert; Salvail, Dany; Lesur, Olivier; Auger‐Messier, Mannix; Sarret, Philippe; Marsault, Éric

doi:10.1021/acs.jmedchem.7b01353

Cited by 33 publications

(45 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This study underlines the possible link between G protein‐independent signaling and hypotensive effect in the apelinergic system . More recently, a rolling loop scan study conducted on apelin‐13 led to the identification of KT01–3 ( 31 ) (Figure F) bridged on the C ‐terminal region of the peptide . 31 exhibits similar affinity compared to the endogenous ligand ( K i 1.1 nM) and is 10‐fold less potent on Gα i1 activation (EC 50 19 nM) and β‐arrestin‐2 recruitment (EC 50 272 nM).…”

Section: Structure–activity Relationship Of Apelin‐13mentioning

confidence: 60%

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

et al. 2018

Self Cite

View full text Add to dashboard Cite

The apelinergic system emerges as an important regulator of cardiovascular functions via its actions on the heart, vasculature, and kidney. It also possesses additional beneficial properties, via its actions on the pancreas and skeletal muscle, on type 2 diabetes. The apelinergic system distinguishes itself by the presence of two structurally distinct sets of endogenous ligands, the Apelins (–13, −17, and −36) and Elabela, which both activate the apelin (APJ) receptor. In the past decade, numerous peptidic ligands have been used to better understand the structure–activity relationship of apelin (and more recently Elabela), providing important tools to rationalize how ligand modifications impact receptor structure and dynamics as well as its downstream signaling. The recently disclosed structure of the apelin receptor in complex with an analogue of apelin‐17 provides an important tool in this quest. In this review, we first summarize the physiopharmacology of the apelinergic system, then, review existing knowledge on the various ligands of the apelin receptor with an emphasis on peptidic ligands, although small molecules are covered as well. Throughout this work, we tried to integrate existing knowledge of ligands’ pharmacological profiles with structure and signaling profile.

show abstract

Section: Structure–activity Relationship Of Apelin‐13mentioning

confidence: 60%

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…A further systematic study of macrocyclization in Pyr 1 ‐apelin‐13 identified the N‐ and C‐termini as preferable sites for cyclization to retain good binding and signaling properties, and to significantly increase plasma stability. In this series, low nM, G αi ‐biased agonists were identified, and they demonstrated, as suggested above, very low hypotensive properties in rats in vivo , as well as strong inotropic properties in the Langendorff isolated perfused heart model …”

Section: Toward Pharmacological Probes and Novel Drugsmentioning

confidence: 64%

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

Marsault

Llorens-Cortes

Iturrioz

et al. 2019

Annals of the New York Academy of Sciences

Self Cite

View full text Add to dashboard Cite

The apelinergic pathway has been generating increasing interest in the past few years for its potential as a therapeutic target in several conditions associated with the cardiovascular and metabolic systems. Indeed, preclinical and, more recently, clinical evidence both point to this G protein-coupled receptor as a target of interest in the treatment of not only cardiovascular disorders such as heart failure, pulmonary arterial hypertension, atherosclerosis, or septic shock, but also of additional conditions such as water retention/hyponatremic disorders, type 2 diabetes, and preeclampsia. While it is a peculiar system with its two classes of endogenous ligand, the apelins and Elabela, its intricacies are a matter of continuing investigation to finely pinpoint its potential and how it enables crosstalk between the vasculature and organ systems of interest. In this perspective article, we first review the current knowledge on the role of the apelinergic pathway in the above systems, as well as the associated therapeutic indications and existing pharmacological tools. We also offer a perspective on the challenges and potential ahead to advance the apelinergic system as a target for therapeutic intervention in several key areas.

show abstract

“…Moreover, KKS has been described as a specific node linking the inflammatory and coagulation responses to microbial infection and thus contributing to the pathogenesis of sepsis 42 . The biological efficiency of the apelin system is therefore compromised under this environmental pressure, given the very short half-lives of endogenous APLNs 43 . Accordingly, a PCA of this cohort revealed that nonsurvivors were widely located within a component corresponding to enhanced apelinergic release-degradation system activity.…”

Section: Discussionmentioning

confidence: 99%

“…Competitive radioligand binding experiments were performed as previously described 43 using [ 125 I]-(pyr 1 )Apelin(APLN)-13 (820 Ci/mmol) prepared with IODO-GEN (1,3,4,6-tetrachloro-3a,6a-diphenyl-glycoluril; Thermo Scientific Pierce, Canada) 49 . In brief, HEK293 cells with surface expression of HA epitope-tagged sheep APJ generated as previously described (ref Murza) were incubated with 0.2 nM radiolabeled APLN-13 and increasing concentrations of cold APLN-13 or ELA synthesized as previously described 50 (10 –11 to 10 –5 M) for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…As previously described 43 , 27 μL of plasma mixed with 6 μL of a 1 mM aqueous solution of APLN-13 or ELA were incubated at 37 °C. Proteolytic degradation was stopped by adding 140 μL of 50% acetonitrile, 50% ethanol, and 0.25 mM N, N-dimethylbenzamide at 0, 0.5, 1, 2, 4, or 6 h. The reaction mixture was filtered by centrifugation at 2,000 rpm with Impact Protein Precipitation Filter plates (Phenomenex, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients

Coquerel

Lamoureux

Chagnon

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

show abstract

A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects

Cited by 33 publications

References 66 publications

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients

Contact Info

Product

Resources

About