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Sanfilippo disease Supported projects Conception of chemical chaperones

• The development and evaluation of chemical chaperones of N-acetylglucosaminidase

(Photo Prof. Matthieu Sollogoub)

((Conducted by Prof. Matthieu Sollogoub’s Franco-British group, UMPC Université Paris 6, UMR CNRS 6514, Poitiers, France, Glycobiology Institute, Oxford, UK))

This ongoing research and development project led by Prof. Sollogoub consists of developing glycosidic inhibitors of N-acetylglucosaminidase, the missing enzyme in MPS IIIB. The idea consists of synthesizing small molecules called chemical chaperones, which are designed to correct the structure and the intra-cellular transport of certain mutated forms of the non-functional enzyme in patients suffering from this form of Sanfilippo disease (MPS IIIB). The objective of this work is to restore the capacity to break down heparan sulfate.

In 2011 a series of compounds were synthesised and evaluated in several enzyme and cell tests. It was rewarding to observe that the two molecules turned out to act as specific inhibitors of N-acetylglucosaminidase. Even more encouraging, one of the two compounds, simply called beta, was found to restore the activity of the incriminated enzyme. It is the first clear proof that the activity of N-acetylglucosaminidase can be restored by the specific action of a molecular chaperone. The ensuing stages of the project will consist of improving the pharmacological characteristics of this molecule, in particular its capacity to reach the central nervous system, as well as increasing its efficacy and its specificity. The objective is to evaluate one of these molecules in an animal model of Sanfilippo disease in order to determine if these new compounds are effective candidate substances for medical use and  ready for clinical testing.

A patent protecting these molecules has been drafted and filed with the European Patent Office.