1,6-epi-cyclophellitol cyclosulfamidate 4 binds competitively to human lysosomal acid α-glucosidase (GAA) and stabilizes recombinant human GAA (rhGAA), potentially representing a valuable therapeutic alternative to miglustat in the treatment of Pompe disease, according to a recently published study in the Journal of the American Chemical Society.

The clinical efficacy of enzyme replacement therapy (ERT) with rhGAA in Pompe disease is limited due to its instability in the plasma and autophagic buildup in skeletal muscle, which has incentivized investigation into therapeutic alternatives.

Pharmacological chaperone therapy (PCT) with drugs such as miglustat involves the reversible inhibition of the mutated active enzyme site and the stabilization of its mature protein fold, and it has shown promise both as monotherapy and as combined therapy with rhGAA.

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Unfortunately, not all patients with Pompe disease carry mutations that respond to PCT. Furthermore, miglustat is not GAA selective and targets many other carbohydrate degradation enzymes.

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“In principle, the ideal pharmacological chaperone in a combined chaperone-ERT setting binds, and stabilizes, recombinant enzyme (here rhGAA) in circulation but is outcompeted by its natural substrate (here lysosomal glycogen) upon reaching its (sub)cellular target,” the authors wrote.

1,6-epi-cyclophellitol cyclosulfate 3 has successfully stabilized α-galactosidase A (α-GalA), involved in the pathogenesis of Fabry disease, through reversible inhibition. Considering that both GAA and α-GalA utilize an identical Koshland double displacement reaction mechanism with C1, the authors hypothesized that a compound with the corresponding α-glc-cyclosulfamidates (1,6-epi-cyclophellitol cyclosulfamidate 4) could act as an enzyme stabilizer in PD.

In vitro results revealed that 1,6-epi-cyclophellitol cyclosulfamidate 4 could prevent rhGAA degradation through the reversible occupation of its active site. In situ studies with fibroblast cultures showed that rhGAA lasted 3 days longer in assays treated with 1,6-epi-cyclophellitol cyclosulfamidate 4. After 4 days, 1,6-epi-cyclophellitol cyclosulfamidate 4 reduced rhGAA degradation by 50%, compared to 5% with miglustat.

The compound also showed effectiveness in preventing plasma degradation of rhGAA. 1,6-epi-cyclophellitol cyclosulfamidate 4 increased plasma rhGAA activity 3-fold compared to that seen in the control group. Plasma treated with 1,6-epi-cyclophellitol cyclosulfamidate 4 showed 2 times more rhGAA activity after 2 hours than plasma treated with miglustat.

“We conclude that cyclosulfamidate 4 presents a superior stabilization and selectivity profile compared to [miglustat], the benchmark compound in clinical combination ERT/PCT trials for the treatment of Pompe disease,” the authors concluded.


Kok K, Kuo CL, Katzy RE, et al. 1,6-epi-cyclophellitol cyclosulfamidate is a bona fide lysosomal α-glucosidase stabilizer for the treatment of Pompe disease. J Am Chem Soc. Published online August 2, 2022. doi:10.1021/jacs.2c05666