Periodic Reporting for period 1 - UniSens (Universal GPCR Activity Sensor for Next Generation Drug Discovery)
Periodo di rendicontazione: 2023-11-01 al 2024-10-31
This project by a consortium of academic labs and small biotech companies concerns a new key innovation for the development of drugs targeting G protein-coupled receptors (GPCRs). GPCRs are the most important class of therapeutic targets, both for current drugs and those under development, covering about a third of the €1.2 trillion pharmaceutical market. Recent research has revealed that GPCRs do not function as simple on/off switches but instead can adopt multiple conformations leading to complex textures of downstream effects. Functionally selective drugs modulate the GPCR structure to stimulate certain downstream pathways over others. In the search for this next generation of better drugs, the pharmaceutical industry currently employs multiple (10+) distinct GPCR assays, performed in non-identical cellular contexts, and misleading readouts from this approach contribute significantly to costly drug failure. Here we propose a radically new single-assay technology platform that will enable detection and functional classification of drug candidates with superior confidence compared to today's approaches. Its unique design supports streamlined drug discovery from the test tube to the native disease-relevant cell, as well as the capacity to efficiently harness artificial intelligence (AI) in the design of better drugs. The technology is based upon highly informative fluorescent sensor reagents that react to different receptor conformations with subtle, flexible changes in their structure. In this Pathfinder project, our main objective is to demonstrate that the conformational fingerprints generated by these sensors correlate to specific cellular signalling profiles, i.e. GPCR activity states (proof of principle). We believe that the UniSens platform will become the standard tool for early drug development and could be a game-changer in the search for safer, more effective drugs.
In RP1, we performed the following:
- Generation of new functionalised fluorophore derivatives with enhanced physicochemical properties (WP2)
- We established all workflows for producing the SensArr reagents that are the basis of the UniSens Technology (WP2)
- We demonstrated that the new SensArrs functionally bind GPCRs; initial data suggest ligand-dependent changes in the SensArr output (WP2)
- We developed a novel tri-scanning confocal microscope that substantially increases the sensitivity of fluorescence detection (WP3)
- We established the data processing workflows and computational models that will be employed to process signalling data (WP5)
- Generation of new functionalised fluorophore derivatives with enhanced physicochemical properties (WP2)
- We established all workflows for producing the SensArr reagents that are the basis of the UniSens Technology (WP2)
- We demonstrated that the new SensArrs functionally bind GPCRs; initial data suggest ligand-dependent changes in the SensArr output (WP2)
- We developed a novel tri-scanning confocal microscope that substantially increases the sensitivity of fluorescence detection (WP3)
- We established the data processing workflows and computational models that will be employed to process signalling data (WP5)