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DEtermination of Orphan Receptor PHysiological Agonists and sigNals

Periodic Reporting for period 4 - DE-ORPHAN (DEtermination of Orphan Receptor PHysiological Agonists and sigNals)

Reporting period: 2019-11-01 to 2020-04-30

G protein-coupled receptors (GPCR) make up both the largest signalling system and drug target families in human, thus of high importance for physiology and medicine. DE-ORPHAN has identified physiological agonist hormones and research tool compounds poorly characterised ‘orphan’ receptors. These receptor ligands open up for exploration of the new physiological signalling systems and present new druggable targets, ligands and mechanisms.
We have developed 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.

The main results are:
1. Discovery of physiological peptide hormones for five GPCRs (Foster et al., Cell 2019).
2. Tool compounds for three receptors that can be used to uncover their pharmacology and function.
3. Unique data and webserver tools in our open access database GPCRdb serving >4,000 users/mon.

So far, the project has led to 20 peer-reviewed articles, 15 invited conference talks by the PI and 4 workshops.
The identified physiological and surrogate ligands open up for characterisation of these important receptors in terms of their function and therapeutic relevance/area. The open access GPCRdb resources is a unique dissemination of data and tools of relevance not only for this project, but the wide 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.