Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance.
Biased G protein-coupled receptor ligands engage subsets of the receptor signals normally stimulated by unbiased agonists. However, it is unclear whether ligand bias can elicit differentiated pharmacology in vivo. Here, we describe the discovery of a potent, selective β-arrestin biased ligand of the angiotensin II type 1 receptor. TRV120027 (Sar-Arg-Val-Tyr-Ile-His-Pro-D-Ala-OH) competitively antagonizes angiotensin II-stimulated G protein signaling, but stimulates β-arrestin recruitment and activates several kinase pathways, including p42/44 mitogen-activated protein kinase, Src, and endothelial nitric-oxide synthase phosphorylation via β-arrestin coupling. Consistent with β-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increased cardiomyocyte contractility in vitro. In rats, TRV120027 reduced mean arterial pressure, as did the unbiased antagonists losartan and telmisartan. However, unlike the unbiased antagonists, which decreased cardiac performance, TRV120027 increased cardiac performance and preserved cardiac stroke volume. These striking differences in vivo between unbiased and β-arrestin biased ligands validate the use of biased ligands to selectively target specific receptor functions in drug discovery.
Violin
Jonathan D
JD
Trevena Inc, King of Prussia, Pennsylvania 19406, USA. jviolin@trevenainc.com
DeWire
Scott M
SM
Yamashita
Dennis
D
Rominger
David H
DH
Nguyen
Lisa
L
Schiller
Kevin
K
Whalen
Erin J
EJ
Gowen
Maxine
M
Lark
Michael W
MW
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects*; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D019390:Arrestins; D009842:Oligopeptides; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; C555535:sarcosine-arginyl-valyl-tyrosyl-lysyl-histidyl-prolyl-alanine; D000804:Angiotensin II; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins; C555534:Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH