Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts.

Autor:	Maccarana M; Department of Medical Biochemistry and Microbiology, University of Uppsala, Husargatan 3, 75123, Uppsala, Sweden., Li B; Beijing Advanced Innovation Centre for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, No. 15 North Third Ring Road East, Chaoyang District, Beijing, 100029, P. R. China., Li H; Department of Medical Biochemistry and Microbiology, University of Uppsala, Husargatan 3, 75123, Uppsala, Sweden., Fang J; GlycoNovo Technologies Co. Ltd., Room 202, Building 83-84, 887 Zuchongzhi Road, Pilot Free Trade Zone, Shanghai 201203, China., Yu M; School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No 8 and 9 Yards, Liangxiang East Road, Fangshan District, Beijing 102488, China., Li JP; Department of Medical Biochemistry and Microbiology, University of Uppsala, Husargatan 3, 75123, Uppsala, Sweden.; SciLifeLab, Uppsala University, Husargatan 3, 75123, Uppsala, Sweden.
Jazyk:	angličtina
Zdroj:	Glycobiology [Glycobiology] 2024 Apr 24; Vol. 34 (6).
DOI:	10.1093/glycob/cwae025
Abstrakt:	Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 μM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients. (© The Author(s) 2024. Published by Oxford University Press.)
Databáze:	MEDLINE
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