Multimerization of DAB-1 onto Au GNPs affords new potent and selective N-acetylgalactosamine-6-sulfatase (GALNS) inhibitors

Year: 2018

Authors: Matassini C., Vanni C., Goti A., Morrone A., Marradi M., Cardona F.

Autors Affiliation: Univ Firenze, Dept Chem Ugo Schiff, Via Lastruccia 3-13, Sesto Fiorentino, FI, Italy; CNR, INO, Via N Carrara 1, Sesto Fiorentino, FI, Italy; LENS, Via N Carrara 1, Sesto Fiorentino, FI, Italy; Univ Bari, Consorzio Interuniv Nazl Ric Metodol & Proc Innov, I-70125 Bari, Italy; Univ Florence, Meyer Childrens Hosp, Neurosci Dept, Paediat Neurol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy; Univ Florence, Dept Neurosci Pharmacol & Child Hlth, Viale Pieraccini 24, I-50139 Florence, Italy; CIC BiomaGUNE, P Miramon 182, Donostia San Sebastian, Spain; CIBER BBN, P Miramon 182, Donostia San Sebastian, Spain; CIDETEC, Biomat Unit, P Miramon 196, Donostia San Sebastian, Spain.

Abstract: Gold glyconanoparticles (Au GNPs) decorated with the natural iminosugar DAB-1 at different densities are reported. These new multivalent iminosugar architectures strongly and selectively inhibit N-acetylgalactosamine-6-sulfatase (GALNS), whose deficiency is connected to the lysosomal storage disease Morquio A. The combination of the dendrimeric technique with the synthetic strategy employed for Au GNP preparation allowed the enhancement of the multivalent presentation of the iminosugar onto the surface of gold nanoparticles, which resulted in the best GALNS inhibitor reported to date (IC50 = 520 nM).

Journal/Review: ORGANIC & BIOMOLECULAR CHEMISTRY

Volume: 16 (44)      Pages from: 8604  to: 8612

More Information: This work was supported by the Italian Ministry of Health (grant Ricerca Finalizzata RF-2011-02347694 to AM and FC) and by the MIUR-Italy (PRIN). Ente Cassa di Risparmio di Firenze is acknowledged for financial support and for a fellowship to CM (grant no. 2016/0845). We also thank the facility of the TEM Platform of CIC biomaGUNE and in particular the Soft Matter Nanotechnology Lab group for TEM analysis performed by Dr Joaquin E. Martinez Porcel. The authors w ish to express their gratitude to AMMeC ONLUS (Associazione Malattie Metaboliche Congenite, Italia) for offering continuing support.
KeyWords: Iminosugar Click Clusters; Gold Nanoparticles; Pharmacological Chaperones; Glycosidase Inhibition; Hyacinthacine A(2); Enzyme Assay; Solid-phase; Multivalent; Glyconanoparticles; Binding
DOI: 10.1039/c8ob02587h

Citations: 19
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