Mechanistic diversity in biased angiotensin receptor ligands - SUMMARY OF WORK Many of the leading drugs for cardiovascular disease target G protein-coupled receptors (GPCRs). For example, angiotensin receptor blockers (ARBs), which are antagonists of the angiotensin II type 1 receptor (AT1R), are frontline therapeutics for hypertension. In recent decades, it has become clear that certain “biased” GPCR ligands can preferentially activate subsets of the various cellular signaling pathways that are initiated by GPCRs. For example, AT1R ligands may be biased towards signaling either through heterotrimeric Gq proteins or b-arrestins. The ability to rationally design biased ligands could revolutionize GPCR drug discovery, but our INCOMPLETE UNDERSTANDING of the mechanisms of these ligands has been a CRITICAL BARRIER to such efforts. Our recent data have unexpectedly revealed that biased ligands from the same pharmacological class can use distinct molecular mechanisms to activate AT1R. Our CENTRAL HYPOTHESIS is that these mechanistic differences among ligands will lead to unanticipated functional differences in their signaling. To test this hypothesis, we will employ interdisciplinary methods to understand the mechanisms of two classes of biased AT1R ligands at the structural, cellular, and systems levels. Specifically, our AIMS are: (1) To determine the functional consequences of mechanistic diversity in “b-arrestin-biased” AT1R ligands; (2) To elucidate the molecular mechanisms of “dualsteric” (bitopic) AT1R ligands; (3) To develop biased dualsteric ligands for endogenous AT1R. The IMPACT of this work is that it could guide the development of AT1R ligands tailored for the treatment of various cardiovascular diseases, as well as the design of safer and more effective drugs targeting other members of the conserved GPCR family.
