Structure-based discovery and optimization of novel angiotensin receptor modulators

The angiotensin II type 1 receptor (AT1R) is a key regulator of cardiovascular and renal function, and it is one of the most important drug targets in the treatment of hypertension. AT1R activation results in G-protein signaling, which leads to increased blood pressure, as well as β- arrestin recruitment, which has beneficial hemodynamic and anti-apoptotic effects including increased cardiac output. Peptide ligands have been developed that induce “biased” signaling, selectively activating β-arrestin while blocking G-protein signaling. These would be ideal therapeutics for treatment of heart failure were it not for their extremely short circulating half-life and low affinity. We aim to overcome these challenges by developing novel small molecule biased agonists of the AT1R as next-generation therapeutics. We will use a newly established high-throughput structural biology platform to optimize a low-affinity small molecule agonist, L162313, to improve its potency and signaling properties through iterative cycles of compound synthesis, signaling assays, and structure determination. In parallel, we will conduct a de novo drug discovery campaign by computational docking, with the goal of identifying entirely new chemical scaffolds that engage with structural elements in the AT1R known to promote β- arrestin-biased signaling. These compounds will be further optimized to improve their functional properties using a structure-guided optimization approach. Ultimately new compounds developed in this proposal will have the potential for outlicensing as therapeutics for heart disease, kidney failure, and related conditions.