Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease

Patrick Weber; Zuzana Mészáros; Denis Jagečić; Valentina Hribljan; Dinko Mitrečić; Pavla Bojarová; Kristýna Slámová; Jiří Vrba; Natalia Kulik; Vladimír Křen; Arnold E. Stütz

doi:10.1039/D2CC02712G

Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease†

Patrick Weber,

^a Zuzana Mészáros,

^bc Denis Jagečić,

^d Valentina Hribljan,

^d Dinko Mitrečić,

^d Pavla Bojarová,

^b Kristýna Slámová,

^b Jiří Vrba,

^e Natalia Kulik,

^b Vladimír Křen

*^b and Arnold E. Stütz

^a

Author affiliations

* Corresponding authors

^a Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, Graz, Austria

^b Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, Praha 4, Czech Republic
E-mail: kren@biomed.cas.cz
Tel: +420 296442510

^c Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 1903/3, Praha 6, Czech Republic

^d Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Šalata 3, Zagreb, Croatia

^e Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc, Czech Republic

Abstract

We developed potent and selective aminocyclopentane-derived inhibitors of human O-N-acetyl-β-D-glucosaminidase (OGA) implicated in Alzheimer's disease. For example compound 13 was a nanomolar OGA inhibitor with 92 000-fold selectivity over human HexB. It was non-toxic and increased protein O-GlcNAcylation in the culture of murine neural cells, showing new alternatives in the treatment of tauopathies.

Chemical Communications

Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease†

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Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease

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