Migalastat (GR181413A) hydrochloride an orally competitive inhibitor of α-galactosidase A, with an IC50 value of 0.04µM[1]. Migalastat hydrochloride targets the mutated form of α-galactosidase A via competitively binding to the enzyme, promoting the transport of the abnormal α-galactosidase A mutant to the lysosome and enhances the activity of enzyme processing globotriaosylceramide (GL-3)[2]. Migalastat hydrochloride has been widely used to increase the level of active α-galactosidase A, and has been employed in the development of new combined therapies[3].
In vitro, Migalastat hydrochloride (1000μM) combined with rhα-galactosidase A (0.5nM) and Fabry patient-derived fibroblasts incubated for 5 hours can increase the intracellular level and activity of α-galactosidase A, and reduce the GL-3 level[4].
In vivo, Migalastat hydrochloride treatment via oral administration at a dose of 100mg/kg/day for 28 days resulted in significant reductions in globotriaosylsphingosine (Lyso-Gb3) levels in kidney, heart, and skin of hR301Q α-Gal A Tg/KO mice[5]. Daily oral administration of 300 mg/kg Migalastat hydrochloride (for 4 weeks) significantly increased the α-galactosidase A activity in hR301Q α-Gal A Tg/KO mice and decreased the GL-3 level[6].
References:
[1] Lenders M, Menke E R, Brand E. Biochemical Amenability in Fabry Patients Under Chaperone Therapy—How and When to Test? M. Lenders et al[J]. BioDrugs, 2024, 38(6): 845-854.
[2] Giugliani R, Waldek S, Germain D P, et al. A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects[J]. Molecular genetics and metabolism, 2013, 109(1): 86-92.
[3] Warnock D G, Bichet D G, Holida M, et al. Oral migalastat HCl leads to greater systemic exposure and tissue levels of active α-galactosidase A in Fabry patients when co-administered with infused agalsidase[J]. PLoS One, 2015, 10(8): e0134341.
[4] Benjamin E R, Khanna R, Schilling A, et al. Co-administration with the pharmacological chaperone AT1001 increases recombinant human α-galactosidase A tissue uptake and improves substrate reduction in Fabry mice[J]. Molecular Therapy, 2012, 20(4): 717-726.
[5] Young-Gqamana B, Brignol N, Chang H H, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients[J]. PLoS One, 2013, 8(3): e57631.
[6] Khanna R, Soska R, Lun Y, et al. The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease[J]. Molecular Therapy, 2010, 18(1): 23-33.
Migalastat (GR181413A) hydrochloride是一种口服的α-半乳糖苷酶A竞争性抑制剂，IC50值为0.04µM[1]。Migalastat hydrochloride通过竞争性结合突变型α-半乳糖苷酶A，促进异常酶蛋白向溶酶体的转运，并增强分解globotriaosylceramide (GL-3)的活性[2]。Migalastat hydrochloride已广泛应用于提升α-半乳糖苷酶A活性水平，并用于开发新型联合疗法[3]。
在体外，将1000µM的Migalastat hydrochloride与rhα-半乳糖苷酶A（0.5nM）共同孵育Fabry患者来源的成纤维细胞5小时，能提高细胞内α-半乳糖苷酶A的含量与活性，并降低GL-3水平[4]。
在体内，每日口服100mg/kg/day剂量的Migalastat hydrochloride持续28天，可显著降低hR301Q α-Gal A Tg/KO小鼠肾脏、心脏和皮肤中的globotriaosylsphingosine (Lyso-Gb3)浓度[5]。每日口服300mg/kg剂量的Migalastat hydrochloride连续4周，能显著提高hR301Q α-Gal A Tg/KO小鼠的α-半乳糖苷酶A活性，并降低GL-3水平[6]。