Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications

Abstract

In the last years it has been strongly highlighted in the literature the important role of the so called "local "renin-angiotensin (RA) and kallikrein-kinin (KK) systems (i.e., present in tissues and organs that are originally unrelated to the classical functions of those systems. The classical roles of RAS and KKS include the control of arterial blood pressure and fluid balance through the action of its vasoactive peptides on G-protein coupled receptors (GPCRs), also known as 7TM receptors. The participation of RA and KK systems, and their receptors in pathological situations that are not related to the classical functions of these systems have been described in the literature (for review see Paul et al., 2006; Costa-Neto et al., 2008), including results from our group on involvement in epilepsy (Pereira et al., 2008, Pereira et al., 2010, Pereira et al., submitted - Hypertension), inflammation (Souza et al., 2007; Souza and Costa-Neto, 2012 ), and cancer (Rodriguez-Ferreira et al., 2012b; Rodrigues-Ferreira et al., 2012b; Dillenburg-Pilla et al., submitted - PloS One). One of the possible explanation for the high medical-pharmaceutical relevance of GPCRs (N.B. about 50% of currently marketed drugs act directly or indirectly by modulating the action of GPCRs), including the diverse functions of these receptors, is their ability to activate different signaling pathways, often with different intensities or even selectively, what is called selective agonism or more currently "biased agonism". Based on that, the main goal of this project is to develop and characterize new ligands/drugs with selective agonistic activity for GPCRs from the RA and KK systems, which then showing to possess pharmacological and functional relevance will enable future biotechnological applications. The new developed agonists will be characterized in cells with heterologous expression of wild-type GPCRs, as previously described by our group (e.g. Costa-Neto et al., 2000, Santos et al., 2004; Reis et al., 2007; Santos et al., 2007; Santos et al., 2008; Oliveira et al., 2011; Reis et al., submitted - PNAS). In a second stage of this project, after the thorough pharmacological and biochemical characterization of the new agonists mechanism of action, those compounds will be evaluated for their actions to regulate the expression of different molecular downstream targets by using transcriptomic microarrays and non-directed proteomic approaches. We believe that the success of this project will allow: i) the discovery of new ligands/drugs with selective properties with pharmaco/biotechnological applications, ii) development of a solid structure for biotechnological development and future discovery of new ligands/drugs with selective action. (AU)