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Sanfilippo disease Supported projects Dev. of inhibitors of galactosidase β and the glucuronidase β

Dev. of inhibitors of galactosidase β and the glucuronidase β

(Photo Prof. Olivier Martin)

Development of inhibitors of galactosidase β and the glucuronidase β as candidate molecular chaperones in in-vitro models of Morquio B and Sly syndromes.
(Programme conducted by the laboratory of Prof. Olivier Martin, University of Orleans, France)

The objective of this project is the development of specific inhibitors of galactosidase β and glucuronidase β, two enzymes whose mutated forms cause Morquio B syndrome (MPS IVB) and Sly syndrome (MPS VII). These two enzymes respectively control the breakdown of keratan sulfate and glycosaminoglycans containing residues of uronic acid. When the activity of these two enzymes is lost or strongly diminished following mutations, the large glucidic structures accumulate in the organism and lead to the development of these two devastating syndromes for affected individuals. To date there is no treatment for these two types of mucopolysaccharidosis.

The project’s working hypothesis is that the inhibitors of these two enzymes would act as molecular chaperones and for certain mutations lead to partial recovery of enzymatic activity.

The experimental work already in progress consists first of all of elaborating and synthesizing potential inhibitors of galactosidase β and glucuronidase β starting from molecules which inhibit the activity of similar enzymes. Once the molecules are produced they will be tested on purified enzymes in order to characterise their specificity, and on cells derived from patients suffering from Morquio B and Sly syndromes, in order to determine if the enzymatic activities can be partially resorted. This work is expected to last one year.