Guanidinium Iminosugars as Glycosidase Inhibitors

Effective drug design to modulate biological processes requires knowledge of how substrates and ligands are recognized by their complementary enzymes and receptors. Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion. Thus, inhibitors of glycan-processing enzymes can be used to target an enzyme in a specific pathway to induce predictable changes in glycosylation.The outcomes of such alterations can then be studied and the information obtained is important to understand what makes an inhibitor useful in the biological process, and how inhibitors having these features can be designed in a way that can then be applied into future therapeutics.2 Lysosomal catabolic pathways involve the well-orchestrated actions of a series of enzymes for proper functioning. Lysosomal enzymes carry out precise biochemical reactions in breaking the substrates into smaller components, which need to be either recycled or excreted by the cell. Abnormal excessive accumulation of non-degraded substrates causes a variety of cellular dysfunctions that can potentially lead to a range of pathologies commonly known as lysosomal storage disorders, generally abbreviated as LSDs.
Gaucher disease (GD) is the most dominant lysosomal storage disease. The condition is caused by a mutation in the glucocerebrosidase gene, which can lead to reduced activity of β-glucocerebrosidase (GBA, GBA1) the enzyme responsible for the hydrolysis of glucosylceramide (GlcCer). A deficiency in GBA activity can result in the progressive accumulation of undegraded glucosylceramide substrate leading to serious clinical symptoms and in some cases neurological complications.
The primary focus for therapeutic strategies has been on reducing the cellular concentration of glycosphingolipids within the lysosome. Among the different therapeutic approaches under investigation at present, pharmacological chaperone therapy (PCT) is an interesting technique in order to restore the balance between the influx and degradation of the accumulated substrate. Pharmacological chaperones are small molecules capable of stabilizing a misfolded enzyme and thus prevent degradation by the Endoplasmic Reticulum Associated Degradation machinery (ERAD). In the case of GD, the mutant GBA enzyme is predisposed to misfolding and premature degradation in the ER but often still retains some degree of catalytic activity. An effective pharmacological chaperone-based treatment for GD would involve the pharmacologically active compound binding to and stabilize the misfolded GBA enzyme, thus facilitating its trafficking from the ER to the lysosome where it can degrade GlcCer. Certain iminosugars are highly potent and selective inhibitors of glycosidases and in some cases reversibly bind to the active site of their target enzyme in a pH-dependent manner. It may seem paradoxical to use an inhibitor to stabilize an enzyme, however, the positive outcomes of such therapeutic approaches proved to be beneficial for patients and can result in final enzyme enhancements. Competitive inhibitors, such as iminosugars, have the ability to template the folding of the affected protein and can be used to prevent misfolding and accelerate its transport to the lysosome.
In this regard, the development of potent, preferably pH-dependent glycosidase inhibitors presents an attractive target for the development of new therapeutics.