2022
DOI: 10.3390/molecules27134008
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Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis

Abstract: GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different p… Show more

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Cited by 3 publications
(3 citation statements)
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“…The compound CV82 showed a negligible percentage of inhibition (33% at 1 mM; Figure 4 A), demonstrating its complete selectivity against the GCase enzyme with respect to the β-Gal enzyme. It is worth noting that the best inhibitory activity does not always correspond to the best chaperone activity on cell lines, as already observed for a series of compounds [ 22 ]. Therefore, we tested the ability of the CV82 compound to increase the β-Gal enzyme activity in the fibroblasts wild type ( Figure 4 B) and with the p.Arg201His/p.Tyr83LeufsX8 and p.Arg201His/p.Ile51Asn mutations from juvenile GM1 patients ( Figure 4 C,D).…”
Section: Resultsmentioning
confidence: 83%
“…The compound CV82 showed a negligible percentage of inhibition (33% at 1 mM; Figure 4 A), demonstrating its complete selectivity against the GCase enzyme with respect to the β-Gal enzyme. It is worth noting that the best inhibitory activity does not always correspond to the best chaperone activity on cell lines, as already observed for a series of compounds [ 22 ]. Therefore, we tested the ability of the CV82 compound to increase the β-Gal enzyme activity in the fibroblasts wild type ( Figure 4 B) and with the p.Arg201His/p.Tyr83LeufsX8 and p.Arg201His/p.Ile51Asn mutations from juvenile GM1 patients ( Figure 4 C,D).…”
Section: Resultsmentioning
confidence: 83%
“…23). 191 Nonetheless, a study using fibroblasts from juvenile GM1-gangliosidosis patients showed that 59 rescues the activity of b-galactosidase (40% at 600 mM) in diseased cells.…”
Section: Galactosidasementioning
confidence: 99%
“…This drug is currently being used in the clinic for a significant number of Fabry disease patients, all harboring missense mutations that cause misfolding of -galactosidase, and has been shown to improve the associated cardiac and renal symptoms [36,37]. And, while no other chaperone molecule has reached the clinic so far, several studies are being performed in other LSDs [38][39][40][41][42].…”
Section: Lysosomal Storage Diseasesmentioning
confidence: 99%