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From the same journal

α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

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Author(s)

  • Marta Artola
  • Christinne Hedberg
  • Rhianna J. Rowland
  • Lluís Raich
  • Kassiani Kytidou
  • Liang Wu
  • Amanda Schaafa
  • Maria Joao Ferraz
  • Gijsbert A. van der Marel
  • Jeroen D. C. Codée
  • Carme Rovira
  • Johannes M. F. G. Aerts
  • Gideon J. Davies
  • Herman S. Overkleeft

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Publication details

JournalChemical Science
DateAccepted/In press - 19 Aug 2019
DateE-pub ahead of print (current) - 20 Aug 2019
Number of pages13
Early online date20/08/19
Original languageEnglish

Abstract

Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo.

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© 2019

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