Fabry disease is a rare lysosomal disorder characterized by deficient or absent α-galactosidase A (α-Gal A) activity resulting from mutations in the GLA gene. Migalastat is a pharmacological chaperone. It stabilizes and facilitates trafficking of amenable mutant forms of α-Gal A from the endoplasmic reticulum to lysosomes and increases its lysosomal activity. Fabry disease is a rare, progressive lysosomal disorder caused by mutations in the GLA gene. GLA encodes the homodimeric glycoprotein, α-galactosidase A. It acts in lysosomes to degrade globotriaosylceramide (GL-3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3). In Fabry disease, the activity of α-galactosidase A is deficient or absent. It leads to progressive accumulation of glycolipids, primarily GL-3 and lyso-Gb3, in the plasma and numerous cell types throughout the body. This leads to a variety of clinical manifestations and phenotypes with potentially life-threatening complications.
Migalastat is a low molecular weight iminosugar analogue of the terminal galactose residue on GL-3. In addition, it binds selectively and reversibly to the active sites of amenable mutant forms of α-galactosidase A enzyme. Thus, migalastat acts as a pharmacological chaperone. It stabilizes migalastat-amenable mutant forms of α-Gal A in the endoplasmic reticulum and facilitating proper trafficking to lysosomes. In summary, Migalastat is a potent and competitive inhibitor of α-Gal A. Moreover, the IC50 is 0.04 μM for human α-Gal A. Furthermore, in Fabry transgenic mice expressing mutant forms of α-Gal A, Migalastat increased α-galactosidase A activity. It also reduces GL-3 and lyso-Gb3 levels in major tissues.
All in all, Migalastat is a potent and competitive inhibitor of α-Gal A with an IC50 of 0.04 μM for human α-Gal A. Thus, Migalastat is a useful tool for the research of Fabry disease.