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Research Paper

Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor

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Pages 1503-1512 | Received 27 Mar 2020, Accepted 29 Jun 2020, Published online: 13 Jul 2020
 

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.

Disclosure statement

The authors declare no conflict of interest, financial or otherwise.

Additional information

Funding

W. L. is grateful for support by the Deutscher Akademischer Austauschdienst (DAAD, research assistantship stipend). Y. B. was funded by Arab-German Young Academy of Sciences and Humanities (AGYA). J. G. is a fellow of the Agency for Innovation by Science and Technology (IWT) of Flanders.