sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

Manuel González-Cuesta; Irene Herrera-González; M Isabel García-Moreno; Roger A Ashmus; David J Vocadlo; José M García Fernández; Eiji Nanba; Katsumi Higaki; Carmen Ortiz Mellet

doi:10.1080/14756366.2022.2073444

sp²-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1364-1374. doi: 10.1080/14756366.2022.2073444.

Authors

Manuel González-Cuesta¹, Irene Herrera-González¹, M Isabel García-Moreno¹, Roger A Ashmus², David J Vocadlo², José M García Fernández³, Eiji Nanba⁴, Katsumi Higaki⁴, Carmen Ortiz Mellet¹

Affiliations

¹ Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, Spain.
² Department of Chemistry and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
³ Instituto de Investigaciones Químicas (IIQ), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Sevilla, Sevilla, Spain.
⁴ Organization for Research Initiative and Promotion, Tottori University, Yonago, Japan.

Abstract

The late-onset form of Tay-Sachs disease displays when the activity levels of human β-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp²-iminosugar glycomimetics related to GalNAc that feature a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and behave as selective nanomolar competitive inhibitors of human Hex A at pH 7 with a ten-fold lower inhibitory potency at pH 5, a good indication for pharmacological chaperoning. They increased the levels of lysosomal HexA activity in Tay-Sachs patient fibroblasts having the G269S mutation, the highest prevalent in late-onset Tay-Sachs disease.

Keywords: Iminosugar; Tay-Sachs; pharmacological chaperone; thiazolidine; thiourea.

MeSH terms

Hexosaminidase A / genetics
Humans
Lysosomes
Piperidines
Tay-Sachs Disease* / drug therapy
Tay-Sachs Disease* / genetics
beta-N-Acetylhexosaminidases

Substances

Piperidines
Hexosaminidase A
beta-N-Acetylhexosaminidases

Grants and funding

This work was financially supported by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” [Grants numbers PID2019-105858RB-I00 and RTI2018-097609-B-C21] and the Junta de Andalucía [Grant number P20_00166]. The authors are grateful to the Canadian Institutes of Health Research [MOP-123341], the Natural Sciences and Engineering Research Council of Canada [RGPIN-06466] and the JSPS KAKENHI Grant 17K10051 for support of this research. DJV thanks the Canada Research Chairs Program for support as a Tier I Canada Research Chair in Chemical Biology. The CITIUS (University of Seville) is also acknowledged for technical support. M.G.-C. and I.H-G. are supported by FPI and FPU fellowships, respectively [Grant numbers BES-2017–079676 and FPU17/03147, funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”]. RAA is supported by a trainee award from the Michael Smith Foundation Health Research (MSFHR).