Report
Teaser, summary, work performed and final results
Periodic Reporting for period 3 - DE-ORPHAN (DEtermination of Orphan Receptor PHysiological Agonists and sigNals)
Teaser
G protein-coupled receptors make up both the largest membrane protein and drug target families. DE-ORPHAN aims to determine the close functional context; specifically physiological agonists and signalling pathways; and provide the first research tool compounds, of orphan...
Summary
G protein-coupled receptors make up both the largest membrane protein and drug target families. DE-ORPHAN aims to determine the close functional context; specifically physiological agonists and signalling pathways; and provide the first research tool compounds, of orphan peptide receptors. About one third of the human GPCRs are so called orphan receptors, meaning that their endogenous agonist (and function) is unknown. Characterisation of orphan receptors can unravel unknown physiological signalling systems and present new druggable targets, ligands and mechanisms.
Work performed
We apply computational methods to identify; physiological ligands that link the receptor to a physiological system, tool compounds for pharmacological characterisation, and G protein inhibitors for effective dissection of the intracellular signalling pathways.
We have published proposed physiological peptide hormones for five GPCRs (Foster et al., Cell 2019).
We have identified tool compounds for three receptors taht will be published in the next, last period.
Finally, we have added data and computational tools in a public community resource, GPCRdb (currently serving 4,000 monthly users).
So far, this project has led to 17 peer-reviewed articles, 10 invited conference talks by the PI and 3 workshops; as detailed in the attached mid-term periodic scientific report.
Final results
The identified physiological and surrogate ligands open up for characterisation of these important receptors in terms of their function and therapeutic relevance/area. At the end of the project, we expect to provide solid validation of the physiological ligands and optimised tool compounds, including antagonist, for pharmacological experiments. The public GPCRdb resources is a unique dissemination of data and tools of relevance not only for this project, but the receptor community. In all, the results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms.