SYNTHESIS OF 1-C-ALKYL-IMINO-D-GALACTITOLS AND RELATED COMPOUNDS AS POTENTIAL THERAPEUTIC AGENTS FOR KRABBE DISEASE

摘要

Krabbe disease is a rare, inherited and fatal illness caused by mutations of β-galacto-cerebrosidase (GALC), a lysosomal enzyme involved in the hydrolysis of several galactolipids. Mutations, often located outside of the catalytic domain, prevent GALC from adopting its native conformation. The misfolded enzyme is thus detected and eliminated from the organism. Its non-hydrolyzed substrate accumulates in the central and peripheral nervous system leading to fatal symptoms. The pharmacological chaperone therapy (PCT) is a new and innovative strategy consisting in the administration at very low concentrations of a small molecule having strong interactions with the enzyme, in order to help it adopt the correct conformation, to prevent it from being eliminated and to allow excess substrate to undergo hydrolysis. Most of the time, molecules active as PCTs are powerful enzyme inhibitors, and iminosugars are known for strongly inhibiting glycosidases. The efficiency of this strategy was recently shown for two lysosomal storage disorders: Fabry and Gaucher diseases.