: Sanfilippo syndrome comprises a group of four genetic diseases due to the lack or decreased activity of enzymes involved in heparan sulfate (HS) catabolism. HS accumulation in lysosomes and other cellular compartments results in tissue and organ dysfunctions, leading to a wide range of clinical symptoms including severe neurodegeneration. To date, no approved treatments for Sanfilippo disease exist. Here, we report the ability of N-substituted l-iminosugars to significantly reduce substrate storage and lysosomal dysfunctions in Sanfilippo fibroblasts and in a neuronal cellular model of Sanfilippo B subtype. Particularly, we found that they increase the levels of defective α-N-acetylglucosaminidase and correct its proper sorting toward the lysosomal compartment. Furthermore, l-iminosugars reduce HS accumulation by downregulating protein levels of exostosin glycosyltransferases. These results highlight an interesting pharmacological potential of these glycomimetics in Sanfilippo syndrome, paving the way for the development of novel therapeutic approaches for the treatment of such incurable disease.

N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome / De Pasquale, Valeria; Esposito, Anna; Scerra, Gianluca; Scarcella, Melania; Ciampa, Mariangela; Luongo, Antonietta; D'Alonzo, Daniele; Guaragna, Annalisa; D'Agostino, Massimo; Pavone, Luigi Michele. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 66:3(2023), pp. 1790-1808. [10.1021/acs.jmedchem.2c01617]

N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome

De Pasquale, Valeria
Co-primo
;
Esposito, Anna
Co-primo
;
Scerra, Gianluca;Scarcella, Melania;Ciampa, Mariangela;D'Alonzo, Daniele;Guaragna, Annalisa
;
D'Agostino, Massimo
;
Pavone, Luigi Michele
Ultimo
2023

Abstract

: Sanfilippo syndrome comprises a group of four genetic diseases due to the lack or decreased activity of enzymes involved in heparan sulfate (HS) catabolism. HS accumulation in lysosomes and other cellular compartments results in tissue and organ dysfunctions, leading to a wide range of clinical symptoms including severe neurodegeneration. To date, no approved treatments for Sanfilippo disease exist. Here, we report the ability of N-substituted l-iminosugars to significantly reduce substrate storage and lysosomal dysfunctions in Sanfilippo fibroblasts and in a neuronal cellular model of Sanfilippo B subtype. Particularly, we found that they increase the levels of defective α-N-acetylglucosaminidase and correct its proper sorting toward the lysosomal compartment. Furthermore, l-iminosugars reduce HS accumulation by downregulating protein levels of exostosin glycosyltransferases. These results highlight an interesting pharmacological potential of these glycomimetics in Sanfilippo syndrome, paving the way for the development of novel therapeutic approaches for the treatment of such incurable disease.
2023
N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome / De Pasquale, Valeria; Esposito, Anna; Scerra, Gianluca; Scarcella, Melania; Ciampa, Mariangela; Luongo, Antonietta; D'Alonzo, Daniele; Guaragna, Annalisa; D'Agostino, Massimo; Pavone, Luigi Michele. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 66:3(2023), pp. 1790-1808. [10.1021/acs.jmedchem.2c01617]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/913438
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 4
  • ???jsp.display-item.citation.isi??? 3
social impact