María Isabel García Moreno works in the research group Carbohydrate Bioorganic Chemistry at the University of Seville. She was appointed Tenured Professor of Organic Chemistry in 2009. Her outstanding contributions revolve around the development of sp2-iminosugars as specific inhibitors of glycosylhydrolases. Ongoing projects include the design of glycomimetics for moderate the activity of glycosidases and the development of new therapies, with special attention to lysosomal storage diseases, inflammation and cancer
GalNAc-related sp2-iminosugars as mutant lysosomal β-hexosaminidase A activity enhancers in late-onset Tay-Sachs disease patients’ fibroblasts.
Dysfuntion of human β-hexosaminidase A (Hex A) results in Tay-Sachs disease (TSD), an autosomal recessive lysosomal storage disorder (LSD) condition associated with phenotypic neurodegeneration, for which no effective treatment options are available. Since many of the TSD-causative mutations do not compromise the catalytic site of Hex A, the development of pharmacological chaperones (PCs) that can stabilize the native folding of the protein despite its anomalous conformation and restore activity appears attractive. Most reported PCs developed for LSDs are competitive inhibitors of the target enzyme; they however exert an effector action by dissociating from the corresponding mature enzyme:inhibitor complex in the presence of an excess of substrate in the lysosomes of patient cells. A main problem is that Hex A inhibitors oftentimes also inhibit the related enzyme O-linked N-acetylglucosaminidase (GlcNAcase; OGA), which represents a serious drawback for translation into the clinics. Based on structural information and the known substrate selectivity profile of HexA and OGA, we have addressed this problem by designing sp2-iminosugar glycomimetics closely related to N-acetylgalactosamine (GalNAc). The new candidates feature either a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and are accessed through a structure diversity-oriented approach. Compounds behaving as selective nanomolar competitive inhibitors of human Hex A at pH 7, with high Hex A/OGA selectivity, and displaying a ten-fold lower inhibitory potency at pH 5 were identified, which should facilitate the dissociation of the Hex A-glycomimetic complex at the lysosome, were the Hex A substrate (namely GM2 ganglioside) accumulates. In agreement with this notion the selected candidates specifically increased the levels of lysosomal Hex A activity in patient fibroblasts having the G269S mutation, the one with the highest prevalence in late-onset Tay-Sachs disease.
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