Article ID Journal Published Year Pages File Type
1993213 Methods 2016 8 Pages PDF
Abstract

•We present general guidelines for the validation of biased GPCR ligands in animal models.•Seven criteria for the validation of biased ligands in vivo are proposed.•Detailed protocol for the evaluation of the effects of biased GPCR ligands on protein phosphorylation in vivo is provided.

The realization that G-protein coupled receptors (GPCR) engage several cell signaling mechanisms simultaneously has led to a multiplication of research aimed at developing biased ligands exerting a selective action on subsets of responses downstream of a given receptor. Several tools have been developed to identify such ligands using recombinant cell systems. However the validation of biased ligand activity in animal models remains a serious challenge. Here we present a general strategy that can be used to validate biased ligand activity in vivo and supports it as a strategy for further drug development. In doing so, we placed special attention on strategies allowing to discriminate between G-protein and beta-arrestin mediated mechanisms. We also underscore differences between in vitro and in vivo systems and suggest avenues for tool development to streamline the translation of biased ligands development to pre-clinical animal models.

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Life Sciences Biochemistry, Genetics and Molecular Biology Biochemistry
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