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

Abstract

A collection of carbohydrate-derived iminosugars belonging to three structurally diversified sub-classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α-carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub-micromolar concentration. In the piperidine iminosugar series, two N-alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5-fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease.

Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases

“…Interestingly, the a-5-C-hexyl-DIR derivative 68 (Fig. 19), which was a much weaker inhibitor of the enzyme (IC 50 109 NOEV, administered orally in water solution (1 mM) to mice expressing human R201C b-Gal ad libitum, produced an increase of enzyme activity and a parallel decrease in G M1 -ganglioside in the cerebral cortex and brainstem. Accumulation of tropomyosin receptor kinase (Trk) receptors, 110 p62 (a protein that regulates the formation of protein aggregates) and ubiquitinated proteins, 111 which also contribute to GM1 pathogenesis, was also reduced after NOEV treatment.…”

Gold nanoparticles are suitable cores for building tunable iminosugar multivalency

“…In particular, PA-GNPs afforded IC 50 values in the low micromolar range (4.0-13.9 mM, Table 1), calculated per iminosugar unit based on their evaluated density on the nanoparticles surface. Taking the N-acetyl derivative of 1 as the monovalent reference compound (N-acetyl-1, 27 IC 50 ¼ 1.7 mM), these results demonstrate that the inhibitory activity properties are retained in these multivalent architectures, besides displaying higher selectivity (see ESI †).…”

Biological activities of 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatives

“…Furthermore, remarkably, pharmacological chaperone activity can ensue at weak to good inhibitory potencies, as is the case for N ‐butyl‐DNJ (IC 50 for GCase 270 μ m ) and castanospermine (IC 50 for GCase 19 μ m ) . Another case in point is represented by compound 23 (Table ) which showed chaperoning activity towards GCase at IC 50 30 μ m …”

“…Of the N ‐substituted 4D derivatives 21 – 27 , it is noted that moderate to good inhibition is recorded and a good selectivity profile with each compound inhibiting generally either one or two glycosidases . Compounds 22 – 27 and the basic scaffolds meso ‐2 and 3D were also assayed against human acid β‐glucosidase (GCase) in human leucocyte homogeneate . Scaffolds meso ‐2 and 3D displayed, respectively, a 65% and 50% inhibition at 1 m m concentration.…”