Abstract
Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A leading to the lysosomal accumulation of cerebroside sulphate (sulphatide) causing subsequent demyelination in patients. The enzyme galactosylceramide (cerebroside) sulphotransferase (CST) catalyses the transfer of a sulphate group from 3′-phosphoadenosine-5'-phosphosulphate (PAPS) to cerebrosides producing sulphatides. Substrate reduction therapy for arylsulphatase A by inhibition of CST was proposed as a promising therapeutic approach. To identify competitive CST inhibitors, we synthesised and investigated analogues of the substrate galactosylceramide with variations at the anomeric position, the acyl substituent and the carbohydrate moiety, and investigated their structure–activity relationships. While most of the compounds behaved as substrates, α-galactosylceramide 16 was identified as the first competitive CST inhibitor. Compound 16 can serve as a new lead structure for the development of drugs for the treatment of this devastating disease, MLD, for which small molecule therapeutics are currently not available.
Highlights
Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A1
This defect leads to the lysosomal accumulation of cerebroside sulphate in various cells such as tubular kidney cells, bile duct epithelia, some neurons, oligodendrocytes and Schwann cells
CST catalyses the transfer of a sulphate group from the coenzyme 30-phosphoadenosine-50-phosphosulphate (PAPS, 2) to galactosylceramide (3) yielding galactosylceramide sulphate (2) and adenosine-30,50-bisphosphate (PAP, 4) (Figure 1)[5,6,7]
Summary
Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A1 This defect leads to the lysosomal accumulation of cerebroside sulphate (sulphatide, 1) in various cells such as tubular kidney cells, bile duct epithelia, some neurons, oligodendrocytes and Schwann cells. There is an urgent need to develop alternative strategies to treat MLD One of these strategies is substrate reduction therapy in which galactosylceramide (cerebroside) sulphotransferase (CST; EC 2.8.2.11), the enzyme which synthesises sulphatide, is inhibited. This would diminish the load of accumulated sulphatide in the patient. CST catalyses the transfer of a sulphate group from the coenzyme 30-phosphoadenosine-50-phosphosulphate (PAPS, 2) to galactosylceramide (3) yielding galactosylceramide sulphate (2) and adenosine-30,50-bisphosphate (PAP, 4) (Figure 1)[5,6,7]
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