TY - JOUR
T1 - Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor
AU - Li, Wenjin
AU - Guillaume, Joren
AU - Baqi, Younis
AU - Wachsmann, Isabell
AU - Gieselmann, Volkmar
AU - Van Calenbergh, Serge
AU - Müller, Christa E.
N1 - Funding Information:
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.
Publisher Copyright:
© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - Capillary electrophoresis (CE)
KW - competitative inhibitor
KW - enzyme assay
KW - galactosyl ceramide analogues
KW - galactosylceramide sulphotransferase (CST)
KW - metachromatic leukodystrophy (MLD)
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U2 - 10.1080/14756366.2020.1791841
DO - 10.1080/14756366.2020.1791841
M3 - Article
C2 - 32657203
AN - SCOPUS:85087891500
SN - 1475-6366
VL - 35
SP - 1503
EP - 1512
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 1
ER -