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FP6

THERA-CAMP — Result In Brief

Project ID: 37189
Funded under: FP6-LIFESCIHEALTH
Country: Germany

Stopping the signals that cause disease

Identification of small molecules to either inhibit or promote biochemical reactions is an expanding field with seemingly limitless potential in the medical arena. An EU-funded project has developed new techniques to identify compounds that will interfere with a basic cellular mechanism at the centre of a range of human diseases.
Stopping the signals that cause disease
Major human diseases including cardiovascular and renal diseases, cancer and diabetes mellitus cause massive mortality and morbidity on a global scale. From a biomedical point of view, they have one chemical pathway network in common – compartmentalised cyclic adenosine monophosphate (cAMP).

Cyclic AMP is generated by adenylyl cyclases (ACs) in response to many signals occurring from outside the cell. The main effector of cAMP is protein kinase A (PKA). Connecting these are akinase anchoring proteins (AKAPs) that coordinate cAMP signalling by tying up PKA to various cell compartment systems such as the plasma membrane and the outer mitochondrial membrane – so-called compartmentalisation.

Both compartmentalisation and any of the protein-protein interactions involved in the biochemical world of cAMP are highly specific and offer a host of drug intervention possibilities. The EU-funded project THERA-CAMP aimed to identify small molecules as potential drug targets that affect the interactions of signalling proteins with proteins responsible for anchoring to cellular compartments.

THERA-CAMP scientists primarily looked for molecules that involve the action of ACs, AKAPs and PKA. The team used novel biosensors based on fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) techniques.

Relevant protein-protein reactions were characterised biochemically using molecular modelling studies. Project scientists also established screening systems to identify small molecule disruptors within compartmentalised cAMP networks.

Using BRET cell-based assays, several leads were discovered into neurological diseases. The scientists discovered a dynamic interaction involving Lis, a protein which when mutated, leads to encephalies. THERA-CAMP also unearthed Ndel1, a protein that interacts with DISC1 which is mutated in schizophrenia.

By screening a library of 20,000 molecules different classes of compounds that either induce or inhibit relocalisation of a cAMP molecule were identified. One example is phosphodiesterase which is linked to chronic obstructive pulmonary disease (COPD), fibrosis and sleep aberrations. In addition, from the same screening, molecules have been identified for therapy in diseases linked to water retention such as chronic heart failure and liver cirrhosis.

The capacity to identify small molecules with surface plasmon resonance (SPR)-based competition assays has proven extremely productive. Around 140 molecules with potential for AKAP-PKA disruption have been described. Interestingly, 20 of these are natural compounds – flavonoids and polyphenols.

THERA-CAMP has opened up a whole new perspective on the mechanics of interference with biochemical cascades that cause disease. Using project research protocols, side-effects of small molecule therapy can be determined more accurately. Moreover, compartmentalised cAMP signalling may be used to treat diseases that do not respond to conventional pharmacotherapy.

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