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<oai_dc:dc schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd">
<dc:title>Potent and Selective Cell-Active Iminosugar Inhibitors of Human α-N-Acetylgalactosaminidase (α-NAGAL)</dc:title>
<dc:creator>Ashmus, Roger A</dc:creator>
<dc:creator>Wang, Yang</dc:creator>
<dc:creator>González-Cuesta, Manuel</dc:creator>
<dc:creator>King, Dustin T</dc:creator>
<dc:creator>Tiet, Ben</dc:creator>
<dc:creator>Chen, Xi</dc:creator>
<dc:creator>Zhu, Yanping</dc:creator>
<dc:creator>Kirk, Bryce</dc:creator>
<dc:creator>García Fernandez, José M</dc:creator>
<dc:creator>Ortiz Mellet, Carmen</dc:creator>
<dc:creator>Britton, Robert</dc:creator>
<dc:creator>Vocadlo, David J</dc:creator>
<dc:contributor>Agencia Estatal de Investigación (España)</dc:contributor>
<dc:contributor>Natural Sciences and Engineering Research Council of Canada</dc:contributor>
<dc:contributor>Ministerio de Ciencia e Innovación (España)</dc:contributor>
<dc:contributor>Junta de Andalucía</dc:contributor>
<dc:contributor>European Commission</dc:contributor>
<dc:contributor>Michael Smith Foundation for Health Research</dc:contributor>
<dc:subject>Azasugars</dc:subject>
<dc:subject>cell-based assay</dc:subject>
<dc:subject>iminosugars</dc:subject>
<dc:subject>lysosomal enzyme inhibitors</dc:subject>
<dc:subject>lysosomal storage disorders (LSDs)</dc:subject>
<dc:description>Glycoside hydrolases (GHs) are a class of enzymes with emerging roles in a range of disease. Selective GH inhibitors are sought to better understand their functions and assess the therapeutic potential of modulating their activities. Iminosugars are a promising class of GH inhibitors but typically lack the selectivity required to accurately perturb biological systems. Here, we describe a concise synthesis of iminosugar inhibitors of N-acetyl-α-galactosaminidase (α-NAGAL), the GH responsible for cleaving terminal α-N-acetylgalactosamine residues from glycoproteins and other glycoconjugates. Starting from non-carbohydrate precursors, this modular synthesis supported the identification of a potent (490 nM) and α-NAGAL selective (∼200-fold) guanidino-containing derivative DGJNGuan. To illustrate the cellular activity of this new inhibitor, we developed a quantitative fluorescence image-based method to measure levels of the Tn-antigen, a cellular glycoprotein substrate of α-NAGAL. Using this assay, we show that DGJNGuan exhibits excellent inhibition of α-NAGAL within cells using patient derived fibroblasts (EC50 =150 nM). Moreover, in vitro and in cell assays to assess levels of lysosomal β-hexosaminidase substrate ganglioside GM2 show that DGJNGuan is selective whereas DGJNAc exhibits off-target inhibition both in vitro and within cells. DGJNGuan is a readily produced and selective tool compound that should prove useful for investigating the physiological roles of α-NAGAL.</dc:description>
<dc:description>The authors thank the Natural Sciences and Engineering Research Council of Canada (RGPIN-2020-05426 to DJV), AEI/10.13039/501100011033 (PID2019-105858RB-I00 to COM), MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” (PID2021-124247OB-C21 to JMGF), and the Junta de Andalucía (P20_00166 and US-1380698 to COM) for financial support. RAA thanks the Michael Smith Foundation for Health Research for a fellowship. MG-C thanks FPI (BES-2017-079676) and University of Seville for fellowships. DJV thanks the Canada Research Chairs for a Tier I Canada Research Chair in Chemical Biology. The Centre for High-Throughput Chemical Biology (HTCB, SFU) and CITIUS (Univ. Seville) are thanked for technical support and for access to core facilities.Dr. Pierre-Andre Gilormini is thanked for expert assistance with graphics.</dc:description>
<dc:description>Peer reviewed</dc:description>
<dc:date>2024-04-24T13:25:56Z</dc:date>
<dc:date>2024-04-24T13:25:56Z</dc:date>
<dc:date>2023-08-04</dc:date>
<dc:type>artículo</dc:type>
<dc:identifier>Chemistry - a European Journal 29(44):e202300982 (2023)</dc:identifier>
<dc:identifier>0947-6539</dc:identifier>
<dc:identifier>http://hdl.handle.net/10261/354875</dc:identifier>
<dc:identifier>10.1002/chem.202300982</dc:identifier>
<dc:identifier>37217457</dc:identifier>
<dc:identifier>2-s2.0-85164102650</dc:identifier>
<dc:identifier>https://api.elsevier.com/content/abstract/scopus_id/85164102650</dc:identifier>
<dc:language>en</dc:language>
<dc:relation>#PLACEHOLDER_PARENT_METADATA_VALUE#</dc:relation>
<dc:relation>#PLACEHOLDER_PARENT_METADATA_VALUE#</dc:relation>
<dc:relation>#PLACEHOLDER_PARENT_METADATA_VALUE#</dc:relation>
<dc:relation>#PLACEHOLDER_PARENT_METADATA_VALUE#</dc:relation>
<dc:relation>info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105858RB-I00/ES/MIMETICOS DE GLICOCONJUGADOS: NUEVAS ESTRATEGIAS EN GLICOMEDICINA DIRIGIDAS A ENFERMEDADES NEUROLOGICAS Y DEL SISTEMA IMMUNE/</dc:relation>
<dc:relation>info:eu-repo/grantAgreement/AEI/10.13039/501100011033</dc:relation>
<dc:relation>info:eu-repo/grantAgreement/MCIN/AEI/10.13039/501100011033</dc:relation>
<dc:relation>info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-124247OB-C21/ES/TRANSPORTADORES DE ADN%2FARN DE NUEVA GENERACION: CAPSIDES MOLECULARES BASADAS EN CARBOHIDRATOS/</dc:relation>
<dc:relation>Chemistry (Weinheim an der Bergstrasse, Germany)</dc:relation>
<dc:relation>Publisher's version</dc:relation>
<dc:relation>https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202300982</dc:relation>
<dc:relation>Sí</dc:relation>
<dc:rights>open</dc:rights>
<dc:format>application/pdf</dc:format>
<dc:publisher>Wiley-VCH</dc:publisher>
</oai_dc:dc>