FEDER - UNICAEN - Design, synthesis and biological evaluation of MT5-MMP inhibitors - FONCT
Kohesio
UNIVERSITE DE CAEN NORMANDIE
Alzheimer's disease, the most common form of senile dementia, affected thirty-five million people worldwide in 2010 and this figure could rise to sixty-five in 2030 with a medical and societal cost estimated at that date at more than $1,100 billion. The only drugs available today, acetylcholinesterase inhibitors, have a purely symptomatic action and their effectiveness also decreases with the progression of the disease. To stop this, numerous studies have been carried out, this time no longer targeting the consequences but the molecular causes of neuronal death. These are becoming better and better known today. They appear numerous and intricate. The main one remains the aggregation of the amyloid peptide causing so-called senile plaques and significant neurotoxicity leading to the cognitive disorders accompanying the disease. This is why a lot of work aimed at preventing amyloid aggregation has been carried out around the world. One of the means undertaken to achieve this was to prevent the formation of the amyloid peptide by inhibiting the cleavage enzymes of its precursor, the APP protein. Numerous beta and gamma secretase inhibitors have been designed and shown to be effective in vitro. Unfortunately, the clinical trials undertaken so far had to be stopped due to the toxicity manifested by these inhibitors linked to the involvement of beta and gamma secretases in numerous other physiological processes. A new enzyme involved in the cleavage of the APP protein has, however, just been discovered. This is the matrix-metallo proteinase MT5, also called n-secretase, at the origin of the formation of another synaptotoxic peptide, the amyloid n alpha peptide, also involved in the neuroinflammation which accompanies Alzheimer's disease. No selective inhibitor of this enzyme has so far been described and the discovery of such an agent sparing beta and gamma secretases would make it possible to verify the potential therapeutic interest residing in this new biological target. This is what the MT5-MMP program intends to carry out, conducted at CERMN in partnership with the Neurobiology of Cellular Interactions and Neurophysiopathology (NICN) unit in Marseille, which has demonstrated the role played by this enzyme in the pathogenesis of Alzheimer's disease and has in vitro models making it possible to evaluate potential inhibitors. This project is partly financed by the revitalization agreement signed between the State and the laboratory Merck Sharp and Dohme and which awarded CERMN a donation of 80,000 euros without any compensation. CERMN was chosen as the only research unit to benefit from this agreement due to its recent work leading to the identification of a promising drug candidate in the treatment of Alzheimer's disease. This project is therefore part of the intelligent specialization area of ​​RIS3 Innovations in Biomedical Sciences and Technologies.
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