Pompe disease is an inborn metabolic myopathy caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA) and characterized by glycogen accumulation in lysosomes causing severe secondary cellular damage resulting in progressive motor handicap and premature death. We have previously determined the high-resolution crystal structure of recombinant human GAA (rhGAA), the standard care of Pompe disease, in its unbound form and in complex with inhibitors . These structures provide the molecular framework for the rationalization of mutations associated with fatal infantile Pompe disease, offering guidance for therapeutic approaches and affording an accurate tool for in silico screening for molecules serving for future therapies. Although since its approval in 2006 enzyme replacement therapy for Pompe disease with rhGAA shows clinical benefits, the treatment is limited by variable patient’s response, insufficient targeting and uptake in muscle tissues and immunogenic reactions. Pharmacological chaperone therapy (PCT), based on the concept that small-molecule ligands may block conformational fluctuations of a partially misfolded protein, rescuing its functional state, has been recognized as an appealing alternative therapeutic approach to ERT. Furthermore, pharmacological chaperones can act as enzyme enhancers when co-administered with rhGAA, by favouring enzyme delivery, stability and maturation, making PCT independent from the type of mutation carried by patients. We had already determined the 3-D structure of rhGAA in complex with the pharmacological chaperone N-acetyl-cysteine  which provided hints of its stabilizing function at the molecular level. Here we will present our latest results on structural studies of rhGAA in complex with small molecules which bear the potential of serving as selective pharmacological chaperones for the treatment of Pompe patients.
- Roig-Zamboni, V.; Cobucci-Ponzano, B.; Iacono R.; Ferrara, M.C.; Germany, S.; Bourne, Y.; Parenti, G.; Moracci, M.; Sulzenbacher, G. Structure of human lysosomal acid α-glucosidase - a guide for the treatment of Pompe disease. Nat. Commun. 2017, 8 (1), 1111.
- Porto, C.; Ferrara, M.C.; Meli, M.; Acampora, E.; Avolio, V.; Rosa, M.; Cobucci-Ponzano, B.; Colombo, G.; Moracci, M.; Andria, G.; Parenti, G. Pharmacological enhancement of α-glucosidase by the allosteric chaperone N-acetylcysteine. Mol. Ther. 2012, 20(12), 2201-2011.