Biased signalling

Picture 1. Most GPCR ligands activate multiple signalling pathways spanning four G protein classes: Gq/11, Gi/o, Gs and G12/13 with 16 subtypes. Furthermore, arrestin proteins modulate GPCR signalling, desensitisation and internalisation.

Picture 2. A biased ligand preferentially actives only one singnalling pathway. A new candidate analgesic drug, oliceridine selectively stimulates the μ-opioid receptor Gi/o pathway, but lacks the ß-arrestin mediated constipation and respiratory depression.

Drug development has an 86% failure rate –mainly due to insufficient efficacy or to side effects. For many GPCRs this could be solved by ‘biased ligands’ which re-route cellular pathways to therapeutic actions away from side effects. However, this huge potential is inaccessible because few GPCRs have biased ligands and we do not yet know the molecular mechanisms to rationally design them

Biased ligands:
The GPCR cluster has/will:
• Made a biased ligand database containing nearly all such ligands in literature.
• Develop new peptide ligands for targets of metabolic disorders.
• Pharmacologically profile the signalling of drugs and commonly used known reference ligands to identify signalling bias.
• Build a virtual screening pipeline to identify candidate biased ligands for many more GPCRs and avail these in a and public database.

Pathway effects:
The GPCR cluster has/will:
• Made an online atlas of the physiological and therapeutic effects of individual GPCR signalling pathways, thereby providing the rationale for which pathways to target in drug discovery and receptor function studies.
• Identify G protein and -arrestin inhibitors – important tools to map more (patho)physiological pathways.

Structures and mechanisms:
The GPCR cluster will determine biased ligand-GPCR structure complexes and develop online tools to ease the generation of GPCR structures bound to G proteins and biased ligands.