FATOKUNEUFP7IIF2010

Blending biophysical and drug discovery platforms to investigate allosterism in G-protein-coupled receptors (GPCRs) and find novel allosteric modulators for neurotherapeutics development

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 Obiettivo del progetto (Objective)

'The global socio-economic and health burden of neurological and neurodegenerative diseases is enormous, impacting overall quality of life and overwhelming available resources. The situation is worrying, considering the predicted future explosion in the aging population. There are currently no ideal drugs to manage these debilitating conditions. This project will thus achieve two major aims:

1. Use biophysical approaches to improve fidelity of pharmacological observations of ligand-receptor interactions for determining mechanisms of action. This will allow investigations of such interactions at the single-cell level, as opposed to current investigations in cell populations, which are less accurate.

2. Use the platform in aim 1 to develop screening assays to identify allosteric modulators of three receptors of exceptional clinical significance: adenosine, metabotropic and GABAB receptors. Allosteric modulators bind to a site on the receptor different from where the endogenous ligand binds, with better selectivity and reduced incidence of side effects compared to orthosteric modulators that bind to the same place as the endogenous ligand.

The inter- and multi-disciplinary project combines pharmacology, biochemistry, molecular and cell biology, medicinal and synthetic chemistry, drug discovery and biophysics. It is intersectoral, featuring collaboration with a spin-out company (CellAura). Allosteric modulators would be developed as pharmacological tools or novel drugs in an arrangement that creates opportunities for longer-term collaboration with the USA, especially Johns Hopkins University.

The Fellow will bring unique expertise in drug discovery and neuroscience. He will enhance his career prospect by engaging in a novel project different in focus and approach from what he undertook previously. The project will attain ERA objectives: product and technology development, patent ownership, product commercialization and creation of spin-outs and job opportunities.'

Introduzione (Teaser)

European scientists have developed specialised molecules for the study of disease pathogenesis of neurodegenerative disorders. These fluorescent probes serve as diagnostic tools and could help in the development of novel therapeutics.

Descrizione progetto (Article)

Neurological and neurodegenerative disorders are steadily increasing in prevalence, posing a heavy socioeconomic burden in European countries. Given the expansion of the ageing population, there is considerable worry since there is a lack of therapeutic treatments for these debilitating conditions.

Compelling evidence implicates the involvement of cell membrane receptors known as G protein-coupled receptors (GPCRs) in neurodegenerative diseases such as Alzheimer's disease. GPCRs are implicated in the amyloid cascade and amyloid-beta mediated toxicity and neuroinflammation observed in Alzheimer's.

The EU-funded FATOKUNEUFP7IIF2010 project focused on the development of fluorescent probes for the visualisation and quantification of GPCRs and their ligands. The idea was to use these molecular tools in drug screening to investigate allosteric interactions. The identification of ligands that pose allosteric effects of GPCRs has been envisaged as a means of eliciting neuroprotection.

The researchers investigated adenosine receptors, metabotropic glutamate receptors and the GABAB receptor closely since their modulation is highly relevant to neurodegeneration. Scientists synthesised a series of fluorescent GPCR ligands and screened them on cell lines in vitro. With the serotonin receptor 5-HT as a model system, appropriate functional assays were developed for assessing the quality of nine different fluorescent ligands. One ligand with antagonist properties for the 5-HT receptor was further processed for imaging purposes and is expected to replace the use of radiolabelled ligands in competitive binding experiments.

With respect to the inhibitory GABAB receptors, scientists identified one fluorescent ligand with antagonist properties which also had excellent photophysical properties for imaging applications. The binding kinetics of these ligands was evaluated by confocal microscopy.

The project has developed molecular tools that promise to be extremely useful in physiological and pharmacological investigations in various pathological conditions. Furthermore, they could be used to understand the kinetics of drugs targeting GPCRs and provide an explanation on the variable behaviour of different drugs at their target receptors.