{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:33:52Z","timestamp":1791441232524,"version":"4.3.3"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T00:00:00Z","timestamp":1715990400000},"content-version":"vor","delay-in-days":24,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2021-01094"],"award-info":[{"award-number":["2021-01094"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish Cancer Research Foundation","award":["CAN211417Pj"],"award-info":[{"award-number":["CAN211417Pj"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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%\u201386% of DS-epi1 activity at 10\u00a0\u03bcM. 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.<\/jats:p>","DOI":"10.1093\/glycob\/cwae025","type":"journal-article","created":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T06:58:17Z","timestamp":1716015497000},"source":"Crossref","is-referenced-by-count":3,"title":["Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3549-8921","authenticated-orcid":false,"given":"Marco","family":"Maccarana","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, University of Uppsala , Husargatan 3, 75123, Uppsala , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4058-180X","authenticated-orcid":false,"given":"Binjie","family":"Li","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-3121","authenticated-orcid":false,"given":"Honglian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, University of Uppsala , Husargatan 3, 75123, Uppsala , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1695-2693","authenticated-orcid":false,"given":"Jianping","family":"Fang","sequence":"additional","affiliation":[{"name":"GlycoNovo Technologies Co. Ltd. , Room 202, Building 83-84, 887 Zuchongzhi Road, Pilot Free Trade Zone, Shanghai 201203 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8906-7476","authenticated-orcid":false,"given":"Mingjia","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Beijing Institute of Technology , No 8 and 9 Yards, Liangxiang East Road, Fangshan District, Beijing 102488 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4255-3581","authenticated-orcid":false,"given":"Jin-ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, University of Uppsala , Husargatan 3, 75123, Uppsala , Sweden"},{"name":"SciLifeLab, Uppsala University , Husargatan 3, 75123, Uppsala , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"issue":"8","key":"2024051805310089100_ref1","doi-asserted-by":"crossref","first-page":"4865","DOI":"10.1007\/s11033-014-3417-x","article-title":"Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways","volume":"41","author":"Azad","year":"2014","journal-title":"Mol Biol Rep"},{"issue":"6","key":"2024051805310089100_ref2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00005-012-0195-9","article-title":"Putative biological mechanisms of efficiency of substrate reduction therapies for mucopolysaccharidoses","volume":"60","author":"Banecka-Majkutewicz","year":"2012","journal-title":"Arch Immunol Ther Exp"},{"issue":"4","key":"2024051805310089100_ref3","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/0003-2697(62)90095-7","article-title":"A modified uronic acid carbazole reaction","volume":"4","author":"Bitter","year":"1962","journal-title":"Anal Biochem"},{"issue":"11","key":"2024051805310089100_ref4","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/s10038-019-0662-9","article-title":"Enzyme replacement therapy for mucopolysaccharidoses; past, present, and future","volume":"64","author":"Chen","year":"2019","journal-title":"J Hum Genet"},{"key":"2024051805310089100_ref5","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1017\/S1462399408000550","article-title":"The mucopolysaccharidoses: a success of molecular medicine","volume":"10","author":"Clarke","year":"2008","journal-title":"Expert Rev Mol Med"},{"issue":"7","key":"2024051805310089100_ref6","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.3390\/ijms17071065","article-title":"Less is more: substrate reduction therapy for lysosomal storage disorders","volume":"17","author":"Coutinho","year":"2016","journal-title":"Int J Mol Sci"},{"issue":"1","key":"2024051805310089100_ref7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3390\/diseases5010005","article-title":"Substrate deprivation therapy to reduce glycosaminoglycan synthesis improves aspects of neurological and skeletal pathology in MPS I mice","volume":"5","author":"Derrick-Roberts","year":"2017","journal-title":"Diseases"},{"issue":"16","key":"2024051805310089100_ref8","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1002\/jcc.10349","article-title":"A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations","volume":"24","author":"Duan","year":"2003","journal-title":"J Comput Chem"},{"issue":"3","key":"2024051805310089100_ref9","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/cbin.11275","article-title":"Changes in cellular processes occurring in mucopolysaccharidoses as underestimated pathomechanisms of these diseases","volume":"45","author":"Gaffke","year":"2021","journal-title":"Cell Biol Int"},{"issue":"8","key":"2024051805310089100_ref10","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.3390\/cells9081838","article-title":"Mucopolysaccharidosis type I: a review of the natural history and molecular pathology","volume":"9","author":"Hampe","year":"2020","journal-title":"Cells"},{"issue":"5","key":"2024051805310089100_ref11","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1039\/D0SC05971D","article-title":"The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms","volume":"12","author":"Hasan","year":"2021","journal-title":"Chem Sci"},{"issue":"4","key":"2024051805310089100_ref12","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nprot.2017.016","article-title":"Genome-scale CRISPR-Cas9 knockout and transcriptional activation screening","volume":"12","author":"Joung","year":"2017","journal-title":"Nat Protoc"},{"issue":"3","key":"2024051805310089100_ref13","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/prot.10104","article-title":"Increasing the precision of comparative models with YASARA NOVA\u2014a self-parameterizing force field","volume":"47","author":"Krieger","year":"2002","journal-title":"Proteins"},{"key":"2024051805310089100_ref14","article-title":"Mucopolysaccharidosis type I","volume":"10","author":"Kubaski","year":"2020","journal-title":"Diagnostics (Basel)"},{"issue":"43","key":"2024051805310089100_ref15","doi-asserted-by":"crossref","first-page":"36283","DOI":"10.1074\/jbc.M112.403360","article-title":"A genetic model of substrate reduction therapy for mucopolysaccharidosis","volume":"287","author":"Lamanna","year":"2012","journal-title":"J Biol Chem"},{"issue":"17","key":"2024051805310089100_ref16","doi-asserted-by":"crossref","first-page":"11560","DOI":"10.1074\/jbc.M513373200","article-title":"Biosynthesis of dermatan sulfate: chondroitin-glucuronate C5-epimerase is identical to SART2","volume":"281","author":"Maccarana","year":"2006","journal-title":"J Biol Chem"},{"issue":"20","key":"2024051805310089100_ref17","doi-asserted-by":"crossref","first-page":"5517","DOI":"10.1128\/MCB.00430-09","article-title":"Dermatan sulfate epimerase 1-deficient mice have reduced content and changed distribution of iduronic acids in dermatan sulfate and an altered collagen structure in skin","volume":"29","author":"Maccarana","year":"2009","journal-title":"Mol Cell Biol"},{"issue":"10","key":"2024051805310089100_ref18","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1093\/glycob\/cwab066","article-title":"Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts","volume":"31","author":"Maccarana","year":"2021","journal-title":"Glycobiology"},{"issue":"12","key":"2024051805310089100_ref19","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1369\/0022155412459857","article-title":"Iduronic acid in chondroitin\/dermatan sulfate: biosynthesis and biological function","volume":"60","author":"Malmstrom","year":"2012","journal-title":"J Histochem Cytochem"},{"issue":"2","key":"2024051805310089100_ref20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ymgme.2013.11.009","article-title":"Standardization of alpha-L-iduronidase enzyme assay with Michaelis-Menten kinetics","volume":"111","author":"Ou","year":"2014","journal-title":"Mol Genet Metab"},{"issue":"3","key":"2024051805310089100_ref21","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1074\/jbc.M805479200","article-title":"Identification of the active site of DS-epimerase 1 and requirement of N-glycosylation for enzyme function","volume":"284","author":"Pacheco","year":"2009","journal-title":"J Biol Chem"},{"issue":"15","key":"2024051805310089100_ref22","doi-asserted-by":"crossref","first-page":"9788","DOI":"10.1074\/jbc.M809339200","article-title":"Two dermatan sulfate epimerases form iduronic acid domains in dermatan sulfate","volume":"284","author":"Pacheco","year":"2009","journal-title":"J Biol Chem"},{"issue":"18","key":"2024051805310089100_ref23","doi-asserted-by":"crossref","first-page":"12376","DOI":"10.1074\/jbc.274.18.12376","article-title":"Characterization of a neutrophil cell surface glycosaminoglycan that mediates binding of platelet factor 4","volume":"274","author":"Petersen","year":"1999","journal-title":"J Biol Chem"},{"issue":"1","key":"2024051805310089100_ref24","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/ana.22643","article-title":"Genistein in Sanfilippo disease: a randomized controlled crossover trial","volume":"71","author":"Ruijter","year":"2012","journal-title":"Ann Neurol"},{"issue":"2","key":"2024051805310089100_ref25","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J Comput Chem"},{"issue":"2","key":"2024051805310089100_ref26","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1039\/C5SC03798K","article-title":"Deciphering the mode of action of the Processive polysaccharide modifying enzyme dermatan Sulfate epimerase 1 by hydrogen-deuterium exchange mass spectrometry","volume":"7","author":"Tykesson","year":"2016","journal-title":"Chem Sci"},{"issue":"8","key":"2024051805310089100_ref27","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S0300-9084(01)01313-X","article-title":"Hexuronyl C5-epimerases in alginate and glycosaminoglycan biosynthesis","volume":"83","author":"Valla","year":"2001","journal-title":"Biochimie"},{"issue":"4","key":"2024051805310089100_ref28","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/prot.20688","article-title":"Molecular docking of balanol to dynamics snapshots of protein kinase a","volume":"61","author":"Wong","year":"2005","journal-title":"Proteins"}],"container-title":["Glycobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/glycob\/article-pdf\/34\/6\/cwae025\/57727876\/cwae025.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/glycob\/article-pdf\/34\/6\/cwae025\/57727876\/cwae025.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T06:58:31Z","timestamp":1716015511000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/glycob\/article\/doi\/10.1093\/glycob\/cwae025\/7676076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,24]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,4,24]]}},"URL":"https:\/\/doi.org\/10.1093\/glycob\/cwae025","relation":{},"ISSN":["1460-2423"],"issn-type":[{"value":"1460-2423","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,6]]},"published":{"date-parts":[[2024,4,24]]},"article-number":"cwae025"}}