Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM1 gangliosidosis

M. Aguilar-Moncayo; T. Takai; K. Higaki; T. Mena-Barragán; Y. Hirano; K. Yura; L. Li; Y. Yu; H. Ninomiya; M. I. García-Moreno; S. Ishii; Y. Sakakibara; K. Ohno; E. Nanba; C. Ortiz Mellet; J. M. García Fernández; Y. Suzuki

doi:10.1039/C2CC32065G

Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM₁ gangliosidosis†

M. Aguilar-Moncayo,‡^a T. Takai,‡^bc K. Higaki,*^b T. Mena-Barragán,^a Y. Hirano,^d K. Yura,^d L. Li,^be Y. Yu,^be H. Ninomiya,^f M. I. García-Moreno,^a S. Ishii,^g Y. Sakakibara,^h K. Ohno,^e E. Nanba,^b C. Ortiz Mellet,*^a J. M. García Fernández*ⁱ and Y. Suzuki*^j

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* Corresponding authors

^a Dpto. Química Orgánica, Fac. de Química, Universidad de Sevilla, c/ Professor García González 1, E-41012 Sevilla, Spain
E-mail: mellet@us.es
Fax: +34-954-624960

^b Division of Functional Genomics, Research Center for Bioscience and Technol., Fac. of Medicine, Tottori University, 86 Nishi-cho, Yonago, Japan
E-mail: kh4060@med.tottori-u.ac.jp
Fax: +81-859-386470

^c Division of Human Genome Science, Dept. of Molecular and Cellular Biology, School of Life Science, Fac. of Medicine, Tottori University, 86 Nishi-cho, Yonago, Japan

^d Center for Informational Biology, Ochanomizu University, 2-1-1 Otsuka, Bunkyoku, Tokyo, Japan

^e Division of Child Neurology, Inst. of Neurological Sciences, Fac. of Medicine, Tottori University, Nishi-cho, Yonago, Japan

^f Dept. of Biomedical Regulation, School of Health Science, Fac. of Medicine, 86 Nishi-cho, Yonago, Japan

^g Department of Matrix Medicine, Fac. of Medicine, Oita University, Oita 879-5593, Japan

^h Dept. of Biosciences and Informatics, Fac. of Science and Technol., Keio University, 3-14-1 Hiyoshi, Kohoku-Ku, Yokohama, Japan

ⁱ Inst. de Investigaciones Químicas (IIQ), CSIC, Américo Vespucio 49, Isla de la Cartuja, E-41092 Seville, Spain
E-mail: jogarcia@iiq.csic.es
Fax: +34-954-460565

^j International University of Health and Welfare Graduate School, 2600-1 Kita Kanemaru, Otawara 324-8501, Japan
E-mail: SuzukiY@iuhw.ac.jp
Fax: +81-287-24-3229

Abstract

Competitive inhibitors of either α-galactosidase (α-Gal) or β-galactosidase (β-Gal) with high affinity and selectivity have been accessed by exploiting aglycone interactions with conformationally locked sp²-iminosugars. Selected compounds were profiled as potent pharmacological chaperones for mutant lysosomal α- and β-Gal associated with Fabry disease and GM₁ gangliosidosis.

Chemical Communications

Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM₁ gangliosidosis†

Abstract

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Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM₁ gangliosidosis

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