Abstract
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition.
Highlights
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively
When the hydroxylated version was synthesized (S221), ceramide galactosyltransferase (CGT) inhibition was restored with an IC50 of 23 μM
This study describes the identification and characterization of S202, a potent and selective inhibitor of CGT with favorable drug-like properties
Summary
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. Lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Krabbe disease and MLD are caused by deficiencies in the lysosomal enzymes galactosylceramidase (GALC) and arylsulfatase A (ARSA), respectively Together, these enzymes catalyze the degradation of major glycosphingolipids of the myelin sheath—galactosylceramide and sulfatide (3-O sulfated galactosylceramide) (Fig. 1). It has been further suggested that the hydroxylated versions of these molecules (2-hydroxy-GalCer and 2-hydroxy-sulfatide) play specific roles in stabilizing tightly packed myelin membranes[10,11,12] Consistent with this hypothesis, rodents and humans deficient in the fatty acid 2-hydroxylase develop leukodystrophy[13,14]. Studies using small molecule glucosylceramide synthase inhibitors to reduce the abundance of the glycolipids that accumulate in Gaucher disease, Fabry disease, GM1
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