title: Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.
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.
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Brame
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Peiran
authors.initials: P
authors.lastname: Yang
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Rubben
authors.initials: R
authors.lastname: Torella
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheriyan
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Robert C
authors.initials: RC
authors.lastname: Glen
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
authors.forename: Ian B
authors.initials: IB
authors.lastname: Wilkinson
authors.affiliation: From the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.). apd10@medschl.cam.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
mesh_terms: D000818:Animals; D058633:Antipyretics; D000075244:Apelin Receptors; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D012107:Research Design; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D058633:Antipyretics; D000075244:Apelin Receptors; C491284:Aplnr protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C586143:apelin 13, Pyr(1)-; D019204:GTP-Binding Proteins
keywords: [Pyr1]apelin-13; pulmonary arterial hypertension; β-arrestin G-protein coupled receptors