A long-acting Betaarrestin â€œbiasedâ€� agonist to selectively activate AT1R to confer cardioprotection during heart failure and COVID-19 cardiovascular complications.
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In patients with Heart Failure (HF) and COVID-19 induced HF, the principal hallmark is a depressed cardiac ejection fraction. Cardiac contractility is mediated through G-Protein Coupled Receptors (GPCR). A critical cardiac GPCR that mediates cardiac contractility is the Angiotensin Type 1 Receptor (AT1R). In the cardiovascular system, homeostasis is maintained by the Renin Angiotensin Aldosterone System (RAAS). An overactivation of the RAAS triggers an increase of Angiotensin II (AngII) and overactivation of AT1R, resulting in vasoconstriction, sodium retention and altered myocyte growth. These factors cause cardiac remodeling (ventricular hypertrophy and dilation) which overall leads to HF. Advancements in drug discovery are leading towards long-acting beta arrestin biased agonist that can simultaneously block AngII - mediated hypertension via AT1R-G alpha q-protein and activate cardioprotective AT1R-Betaarrestin. Activation of AT1R-beta arrestin will provide better therapeutic outcomes than other currently available non-selective drugs. At least two signaling pathways have been characterized for AT1Rs, G alpha q-protein and beta arrestin2. Signaling through the canonical pathway, AngII binds to AT1Rs to recruit Galphaq which causes cell injury. Alternatively, AngII binds to AT1Rs to recruit beta arrestin2 and induces cell protection. Our work will characterize the pharmacological properties of our synthesized peptide-based drugs for beta arrestin2 biased agonism to AT1Rs. We expect to develop a therapeutic drug that provides greater selectivity to ATR1-beta arrestinmediated signaling to increase cardiac contractility in failing hearts and prevent myocardial infarction in patients with COVID-19.