β-Arrestin–Biased Angiotensin II Receptor Agonists for COVID-19

We recently published “β-Arrestin–Biased Angiotensin II Receptor Agonists for COVID-19” in Circulation.

Acutely 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. This strategy mimics built-in regulatory mechanisms of the RAAS system and can be achieved with a drug candidate with established safety in humans.