Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, G_M1-gangliosidosis and Fabry diseases

Abstract

Lysosomal storage disorders (LSDs) are often caused by mutations that destabilize native folding and impair the trafficking of enzymes, leading to premature endoplasmic reticulum (ER)-associated degradation, deficiencies of specific hydrolytic functions and aberrant storage of metabolites in the lysosomes. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are available for a few of these conditions, but most remain orphan. A main difficulty is that virtually all LSDs involve neurological decline and neither proteins nor the current SRT drugs can cross the blood-brain barrier. Twenty years ago a new therapeutic paradigm better suited for neuropathic LSDs was launched, namely pharmacological chaperone (PC) therapy. PCs are small molecules capable of binding to the mutant protein at the ER, inducing proper folding, restoring trafficking and increasing enzyme activity and substrate processing in the lysosome. In many LSDs the mutated protein is a glycosidase and the accumulated substrate is an oligo- or polysaccharide or a glycoconjugate, e.g. a glycosphingolipid. Although it might appear counterintuitive, substrate analogues (glycomimetics) behaving as competitive glycosidase inhibitors are good candidates to perform PC tasks. The advancements in the knowledge of the molecular basis of LSDs, including enzyme structures, binding modes, trafficking pathways and substrate processing mechanisms, have been put forward to optimize PC selectivity and efficacy. Moreover, the chemical versatility of glycomimetics and the variety of structures at hand allow simultaneous optimization of chaperone and pharmacokinetic properties. In this Feature Article we review the advancements made in this field in the last few years and the future outlook through the lessons taught by three archetypical LSDs: Gaucher disease, GM1-gangliosidosis and Fabry disease.

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

“…The finding that PGRN acts as a co-chaperone of HSP70 and is required for disaggregation of GCase, together with the facts that chaperone-based treatments aiming to enhance GCase lysosomal localization have proven to be a promising alternative to enzyme replacement treatment (ERT) and substrate reduction therapy (SRT) for GD (Zimran et al, 2013, Sanchez-Fernandez et al, 2016, Jung et al, 2016, Mena-Barragan et al, 2015), and recombinant HSP70 has been shown to effectively correct altered lysosomal stability seen in Niemann–Pick B disease (NPD) (Kirkegaard et al, 2010), promoted us to examine whether PGRN would have therapeutic effects in GD. Indeed, we have found that recombinant PGRN protein is therapeutic against Gaucher disease (Jian et al, 2016).…”

Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned?

“…As discussed above, ERT has the disadvantage of being expensive; in addition, it does not impact neurological symptoms due to its inability to cross the blood–brain barrier due to its size. Therefore, screening for smaller compounds or developing them though design is a promising approach, and a number of compounds with various chemistries have been developed [103,104]. Some of these compounds have chaperone activity and increase levels of active GCase by enhancing correct folding during trafficking to the lysosome, but others may act though alternative mechanisms.…”

The neurological manifestations of Fabry disease. A review

“…В настоящее время развиваются новые терапевтиче-ские направления -лечение белками-шаперонами и ген-ная терапия [126][127][128][129][130][131][132][133][134]. Также проводятся исследования комбинации сапосина В с модифицированной α-N-ацетил-галактозаминидазой [135].…”