Therapeutic Strategies for Gaucher Disease: Miglustat (NB-DNJ) as a Pharmacological Chaperone for Glucocerebrosidase and the Different Thermostability of Velaglucerase Alfa and Imiglucerase

• DOI: 10.1021/mp200313e
• Publication Date: 2011-10-11T16:24:46Z
• Authors: Olga Abian; Pilar Alfonso; Adrian Velazquez-...; Pilar Giraldo; Miguel Pocovi; Javier Sancho
• Keywords: Glycosphingolipid; Substrate reduction therapy

Gaucher disease (GD) is a disorder of glycosphingolipid metabolism caused by deficiency lysosomal glucocerebrosidase (GlcCerase) activity, due to conformationally or functionally defective variants, resulting in progressive deposition glycosylceramide macrophages. The glucose analogue, N-butyldeoxynojirimycin (NB-DNJ, miglustat), an inhibitor the ceramide-specific glycosyltransferase, which catalyzes first step biosynthesis and currently approved for oral treatment type 1 GD. In previous work, we found GlcCerase activity increase cell cultures presence NB-DNJ, could imply that this compound not only substrate reducer but also pharmacological chaperone degradation. work compare imiglucerase (the enzyme used replacement therapy) velaglucerase alfa (a novel therapeutic form) terms conformational stability enzymatic as well effect NB-DNJ on them. interaction between these enzymes was studied isothermal titration calorimetry. Our results reveal that, although exhibit very similar profiles, shows higher vitro thermal less prone aggregation/precipitation, be advantageous storage clinical administration. addition, show at neutral pH binds enhances both enzymes, while mildly acidic conditions it does bind These support potential role chaperone, susceptible being part pharmaceutical formulation combination therapy GD future.