Descrizione del progetto
Recettori orfani: uno strumento bioinformatico trova agonisti e vie di segnalazione
Molti farmaci agiscono legando i recettori della membrana cellulare, perciò la conoscenza dei loro agonisti e delle loro funzioni consente di sviluppare trattamenti mirati. I recettori accoppiati alle proteine G (GPCR) sono il gruppo di recettori della membrana più grande e diversificato presente negli eucarioti, oltre che un bersaglio farmaceutico cruciale. Pur essendo altamente conservati dal punto di vista strutturale, legano un’enorme varietà di molecole di segnalazione. Ad esempio, gli esseri umani hanno circa 1 000 GPRC, ognuno dei quali lega una molecola altamente specifica. Non sorprende, dunque, che molti GPRC siano recettori cosiddetti orfani, ossia i loro agonisti e le loro funzioni sono sconosciuti. L’ambizioso progetto DE-ORPHAN, finanziato dal Consiglio europeo della ricerca, fornirà il primo strumento bioinformatico e la prima tecnica di screening in grado di determinare le vie di segnalazione e gli agonisti dei GPRC orfani.
Obiettivo
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 signaling pathways; and provide the first research tool compounds, of orphan peptide receptors.
Determination of physiological agonists (aka de-orphanization), by high-throughput screening has largely failed. We will introduce a new research strategy: 1) developing highly innovative bioinformatics methods for handpicking of all orphan receptor targets and candidate ligand screening libraries; and 2) employing a screening technique that can measure all signaling pathways simultaneously.
The first potent and selective pharmacological tool compounds will be identified by chemoinformatic design of focused screening libraries. We will establish the ligands’ structure-activity relationships important for biological activity and further optimization towards drugs.
The first potent and selective Gs- and G12/13 protein inhibitors will be designed by structure-based re-optimization from a recent crystal structure of a Gq-inhibitor complex, and applied to determine orphan receptor signaling pathways and ligand pathway-bias. They will open up for efficient dissection of important signaling networks and development of drugs with fewer side effects.
DE-ORPHANs design hypotheses are based on unique computational methods to analyze protein and ligand similarities and are founded on genomic and protein sequences, structural data and ligands. The interdisciplinary research strategy applies multiple ligands acting independently but in concert to provide complementary receptor characterization. The results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms. Which physiological insights and therapeutic breakthroughs will we witness when these receptors find their place in human pharmacology and medicine?
Campo scientifico
- natural sciencesbiological sciencescell biologycell signaling
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencescomputer and information sciencescomputational science
- natural sciencescomputer and information sciencesartificial intelligencemachine learning
- medical and health sciencesbasic medicinepharmacology and pharmacy
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
1165 Kobenhavn
Danimarca