Progress on the development of Class A GPCR-biased ligands

Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numer- ous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the...

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Detalles Bibliográficos
Autores: Morales, Paula, Scharf, Magdalena M., Bermudez, Marcel, Egyed, Attila, Franco, Rafael, Hansen, Olivia K., Jagerovic, Nadine, Jakubík, Jan, Keserű, György M., Kiss, Dóra Judit, Kozielewicz, Pawel, Larsen, Olav, Majellaro, Maria, Mallo-Abreu, Ana, Navarro, Gemma, Prieto-Díaz, Rubén, Rosenkilde, Mette M., Sotelo, Eddy, Stark, Holger, Werner, Tobias, Wingler, Laura M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/367641
Acceso en línea:http://hdl.handle.net/10261/367641
Access Level:acceso abierto
Palabra clave:Biased signalling
Functionally selective ligands
G protein-coupled receptors
GPCR modulator
Descripción
Sumario:Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numer- ous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signal- ling has opened up new pharmacological avenues holding promise for safer therapeu- tics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this prefer- ential coupling is at different stages depending on the Class A GPCR family. There- fore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.

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