Jayce Technology to decipher receptor biology and pharmacology

Abstract

Manon Kiry, Serge Brand, Alexandre Peter, Urs Luthi and Xavier Leroy* Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland *Corresponding author: xavier.leroy@actelion.com Introduction G-Protein Coupled Receptor Pharmacology was following classical models assuming that agonists at a particular receptor elicit effects through a single mechanism of activation, implying a single activated conformation of the agonist-occupied receptor. This assumption led to the standard nomenclature of GPCR modulators based on affinity and efficacy, and to their classification as full agonist, partial agonist, neutral antagonist, or inverse agonist. However a receptor can engage a variety of biochemical responses and different agonists can elicit different patterns of these responses. Ligands should therefore be classified on the basis of their individual effects in the cell, instead of being either an agonist or an antagonist. The current challenge in the GPCR drug discovery field is based on the development and the implementation of assays that would lead to the discovery of biased or pathways selective agonists in a pro-active and prospective manner. For this achievement, we have developed assays aiming at the characterization of GPCR signaling pathways. Actelion’s JAYCE platform was developed to generate biological information delineating beneficial and adverse signaling pathways at specific receptors and identifies ligands that activate only the pathways associated with therapeutic benefit.