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

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
• pharmacological chaperone
• thiourea
• thiazolidine
• Tay-Sachs

Author contributions

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

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).