A Systematic Investigation of Iminosugar Click Clusters as Pharmacological Chaperones for the Treatment of Gaucher Disease

Abstract

A series of 18 mono- to 14-valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of β-glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected iminosugar cluster has been obtained with a tetravalent 1-deoxynojirimycin (DNJ) analogue (3.3-fold increase at 10 μM). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0-fold instead of 2.4-fold) at a cellular concentration (1 μM) reduced by one order of magnitude.

Human Acid β‐Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

“…However,t he data do not allow ac lear-cut conclusion concerning the role of the alkyl chain. Indeed,t he best inhibitor (21,I C 50 = 720 nm)h as aC 12 chain at the a-position, whereas the same chain at the nitrogen atom (22)r esulted in an increase in IC 50 (4. 3 mm). However,i ntroductiono fj ust am ethyl group on the latter resulted in much better inhibition (23, IC 50 = 940 nm).…”

The clinical management of type 2 Gaucher disease

“…Currently, there is an effort to identify candidate molecules [62,63]. However, this treatment will be helpful only for mutations in GBA1 that result in an unstable mutant protein and may not be appropriate for patients with null alleles.…”

Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases: Successes, Failures, and Unexpected Progress Made in Organic Synthesis

“…Acetylation of the trivalent iminosugar 85 to give the corresponding peracetylated prodrug 86 gave a pharmacological chaperon with higher enzyme activity increases (3.0-fold instead of 2.4-fold) at cellular concentrations reduced by one order of magnitude. 108 On the basis of these preliminary results, we hope that future studies combining prodrug and multivalent strategies will provide a new generation of potent pharmacological chaperones for the treatment of lysosomal diseases.…”

“…108 Systems of lower valency (three-to four-valent), as well as acetylated analogues designed as potential prodrugs, were prepared with the aim of facilitating cellular uptake. Small but significant multivalent effects in GCase inhibition (~2 on a molar basis) were observed for only two of the iminosugar clusters: the four-valent DIX cluster 84 and the DNJ-cyclodextrin conjugate 81.…”