Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase
Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme <i>N</i>-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM<sup&g...
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2025-05-01
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| author | Maria Giulia Davighi Francesca Clemente Giampiero D’Adamio Macarena Martínez-Bailén Alessio Morano Andrea Goti Amelia Morrone Camilla Matassini Francesca Cardona |
| author_facet | Maria Giulia Davighi Francesca Clemente Giampiero D’Adamio Macarena Martínez-Bailén Alessio Morano Andrea Goti Amelia Morrone Camilla Matassini Francesca Cardona |
| author_sort | Maria Giulia Davighi |
| collection | DOAJ |
| description | Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme <i>N</i>-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM<sup>®</sup> (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers <b>1</b> and <b>36</b> as the most promising compounds, able both to bind the native enzyme with IC<sub>50</sub> in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy. |
| format | Article |
| id | doaj-art-9c39481b8e1e47fca223a3cacc92ac90 |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Molecules |
| spelling | doaj-art-9c39481b8e1e47fca223a3cacc92ac902025-08-20T03:48:02ZengMDPI AGMolecules1420-30492025-05-013010222210.3390/molecules30102222Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-SulfataseMaria Giulia Davighi0Francesca Clemente1Giampiero D’Adamio2Macarena Martínez-Bailén3Alessio Morano4Andrea Goti5Amelia Morrone6Camilla Matassini7Francesca Cardona8Department of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyLaboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children’s Hospital IRCCS, Viale Pieraccini 24, 50139 Firenze, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “U. Schiff” (DICUS), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyMorquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme <i>N</i>-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM<sup>®</sup> (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers <b>1</b> and <b>36</b> as the most promising compounds, able both to bind the native enzyme with IC<sub>50</sub> in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy.https://www.mdpi.com/1420-3049/30/10/2222Morquio A<i>N</i>-acetylgalactosamine 6-sulfataseenzyme stabilizersiminosugarsdendrimersmultivalent glycomimetics |
| spellingShingle | Maria Giulia Davighi Francesca Clemente Giampiero D’Adamio Macarena Martínez-Bailén Alessio Morano Andrea Goti Amelia Morrone Camilla Matassini Francesca Cardona Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase Molecules Morquio A <i>N</i>-acetylgalactosamine 6-sulfatase enzyme stabilizers iminosugars dendrimers multivalent glycomimetics |
| title | Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase |
| title_full | Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase |
| title_fullStr | Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase |
| title_full_unstemmed | Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase |
| title_short | Exploring Multivalent Architectures for Binding and Stabilization of <i>N</i>-Acetylgalactosamine 6-Sulfatase |
| title_sort | exploring multivalent architectures for binding and stabilization of i n i acetylgalactosamine 6 sulfatase |
| topic | Morquio A <i>N</i>-acetylgalactosamine 6-sulfatase enzyme stabilizers iminosugars dendrimers multivalent glycomimetics |
| url | https://www.mdpi.com/1420-3049/30/10/2222 |
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