β-Arrestin–Biased Angiotensin II Receptor Agonists for COVID-19
Authors: Aashish Manglik, Laura M. Wingler, Howard A. Rockman, Robert J. Lefkowitz
Journal: Circulation (2020)

cutely decompensated pulmonary and cardiovascular physiology secondary to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection presents one of the gravest threats to human wellbeing in the past century.The most expeditious route to develop urgently needed therapeutic options for this disease is to repurpose drugs known to be safe in humans.SARS-CoV-2 dysregulates renin-angiotensin-aldosterone system (RAAS) homeostasis, elevating angiotensin II (Ang II) levels.Because hyperactivation of the Ang II type 1 receptor (AT1R) appears to be a major contributor to adverse outcomes in patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS), approaches to dampen excess Ang II activity are currently in clinical trials for COVID-19, including the angiotensin receptor blocker losartan.Sustained activation of AT1R by its endogenous ligand, the octapeptide hormone Ang II, leads to heterotrimeric Gq protein signaling that culminates in potent vasoconstriction, cardiomyocyte hypertrophy, and fibrosis in the heart and lungs.However, the pleiotropic signaling downstream of the AT1R includes not only vasoconstrictive but also cardioprotective pathways.Therefore, we propose that an even more effective therapeutic option for severe acute COVID-19 infections would be to selectively modulate rather than to categorically block AT1R signaling, a concept known as biased signaling (Figure).This strategy mimics built-in regulatory mechanisms of the RAAS system and can be achieved with a drug candidate with established safety in humans.The traditional model for activation of G protein-coupled receptors involves the binding of a hormone to the receptor, which induces coupling to a G protein transducer to stimulate the production of second messengers that result in cellular and physiological responses.More recently, it has been appreciated that G proteincoupled receptor signaling involves not only G protein transducer activation but also the recruitment and activation of another adaptor and scaffold protein known as β-arrestin.The ability to direct a G protein-coupled receptor to selectively signal through a G protein-mediated pathway or a β-arrestin-mediated pathway is known as biased signaling (Figure).In this context, AT1R stimulates cellular signaling not only via Gq proteins but also via β-arrestins.However, in contrast to Gq signaling that can lead to vasoconstriction, increased vascular permeability, fibrosis, and acute organ damage in the heart, lungs, and kidneys, β-arrestin-mediated AT1R signaling has beneficial anti-inflammatory, antiapoptotic, and vasodilatory effects 1 (Figure).Whereas Ang II activates both the Gq and β-arrestin signaling arms, certain β-arrestin-biased ligands of the AT1R are able to selectively activate only β-arrestin pathways.The cellular receptor mediating viral entry of both SARS-CoV and SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2), which plays a direct role in RAAS homeostasis by cleaving a single residue from Ang II to generate Ang(1-7) (Figure).