New ligands of angiotensin II AT1 receptor with non-canonical signaling pathways activation potential: large-scale development and characterization

Abstract

G-protein coupled receptors (GPCRs) are important pharmacological targets in all clinical areas, for controlling many physiological processes. Currently, around 50% of drugs on the market act directly or indirectly through GPCRs. Large pharmaceutical companies are looking for new ligands targeting these receptors that show potential as new medicines. Recently the literature has highlighted studies showing that beta-arrestins proteins in addition to acting in GPCR desensitization and internalization perform a second function in the receptor signal transduction, anchoring signaling pathways components that are different from the classical pathway. Some ligands have been described as preferred activators of the pathway of beta-arrestins, thus being called "biased agonists". In vitro studies associated with in vivo models for the study of cardiovascular disease reveal that selective binding to beta-arrestin can exhibit significant effects protecting cardiac function. Considering the importance of the modulation of the renin-angiotensin system for the treatment of cardiovascular diseases, the discovery of new ligands that act on receptors for angiotensin II type 1 (AT1) with selectivity for non-canonical pathways may compose a unique new class of drugs, which act as blockers of canonical pathways, preventing deleterious effects, while positively modulate beneficial functions through non-canonical signaling pathways. This strategy is very important to increase knowledge about the modulations that each pathway plays in the control of physiological and pathological processes, and allows the development of new ligands/medicines with selective action targeting GPCRs. Current technological advances of "High-Content Screening" (HCS) techniques allow us to achieve this goal by large-scale searching for "biased agonists" for AT1 receptors, as proposed in this project.