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Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.


Type

Article

Change log

Authors

Brame, Aimee L 
Maguire, Janet J 
Yang, Peiran 
Dyson, Alex 
Torella, Rubben 

Abstract

[Pyr(1)]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein-coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or β-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In β-arrestin and internalization assays (G-protein-independent), MM07 was 2 orders of magnitude less potent than [Pyr(1)]apelin-13. In a G-protein-dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr(1)]apelin-13 9.93±0.24; MM07 9.54±0.42) and maximum responses with a resulting bias for MM07 of ≈350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr(1)]apelin-13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr(1)]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental β-arrestin-dependent pathways.

Description

Keywords

[Pyr1]apelin-13, pulmonary arterial hypertension, β-arrestin G-protein coupled receptors, Animals, Antipyretics, Apelin Receptors, Disease Models, Animal, GTP-Binding Proteins, Humans, Hypertension, Pulmonary, Intercellular Signaling Peptides and Proteins, Male, Rats, Rats, Wistar, Receptors, G-Protein-Coupled, Research Design, Saphenous Vein, Vasodilation

Journal Title

Hypertension

Conference Name

Journal ISSN

0194-911X
1524-4563

Volume Title

65

Publisher

Ovid Technologies (Wolters Kluwer Health)
Sponsorship
Wellcome Trust (096822/Z/11/Z)
British Heart Foundation (None)
Wellcome Trust (097114/Z/11/Z)
Medical Research Council (MC_PC_12012)
Medical Research Council (MC_PC_13059)
Wellcome Trust (096822/Z/11/A)
Wellcome Trust (085686/Z/08/J)
British Heart Foundation (None)
We acknowledge the Wellcome Trust Programmes in Translational Medicines and Therapeutics (085686) and in Metabolic and Cardiovascular Disease (096822/Z/11/Z), the British Heart Foundation PG/09/050/27734, the Medical Research Council, the Pulmonary Hypertension Association, and the National Institute for Health Research Cambridge Biomedical Research Centre.