Pharmacological Chaperones for the Treatment of α‑Mannosidosis

α-Mannosidosis
(AM) results from deficient lysosomal α-mannosidase
(LAMAN) activity and subsequent substrate accumulation in the lysosome,
leading to severe pathology. Many of the AM-causative mutations compromise
enzyme folding and could be rescued with purpose-designed pharmacological
chaperones (PCs). We found that PCs combining a LAMAN glycone-binding
motif based on the 5N,6O-oxomethylidenemannojirimycin
(OMJ) glycomimetic core and different aglycones, in either mono- or
multivalent displays, elicit binding modes involving glycone and nonglycone
enzyme regions that reinforce the protein folding and stabilization
potential. Multivalent derivatives exhibited potent enzyme inhibition
that generally prevailed over the chaperone effect. On the contrary,
monovalent OMJ derivatives with LAMAN aglycone binding area-fitting
substituents proved effective as activity enhancers for several mutant
LAMAN forms in AM patient fibroblasts and/or transfected MAN2B1-KO cells. This translated into a significant
improvement in endosomal/lysosomal function, reverting not only the
primary LAMAN substrate accumulation but also the additional downstream
consequences such as cholesterol accumulation.