In vivo veritas, the next frontier for functionally selective GPCR ligands

Methods : a Companion to Methods in Enzymology
Jean Martin Beaulieu

Abstract

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.

References

Apr 30, 2003·Neuron·Raul R GainetdinovRichard T Premont
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Jan 15, 2008·Cell·Jean-Martin BeaulieuMarc G Caron
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Apr 19, 2015·Methods : a Companion to Methods in Enzymology·Yoon NamkungStephane A Laporte

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Citations

Aug 31, 2018·PloS One·Davide MalfaciniGirolamo Calo'
Oct 28, 2017·Nature Reviews. Drug Discovery·Alexander S HauserDavid E Gloriam

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