In recent years, the function of
pharmacological chaperones as
a “thermodynamic stabilizer” has been attracting attention
in combination therapy. The coadministration of a pharmacological
chaperone and recombinant human acid α-glucosidase (rhGAA) leads
to improved stability and maturation by binding to the folded state
of the rhGAA and thereby promotes enzyme delivery. This study provides
the first example of a strategy to design a high-affinity ligand toward
lysosomal acid α-glucosidase (GAA) focusing on alkyl branches
on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced
a nanomolar affinity for GAA with a K
i value of 0.0047 μM, which is 13-fold more potent than DNJ.
The protein thermal shift assay revealed that 10 μM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation
temperature (T
m) to 73.6 °C from
58.6 °C in the absence of the ligand, significantly improving
the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ
dose dependency increased intracellular GAA activities in Pompe patient’s
fibroblasts with the M519V mutation. The introduction of C5 alkyl
branches on DNJ provides a new molecular strategy for pharmacological
chaperone therapy for Pompe disease, which may lead to the development
of higher-affinity and practically useful chaperones.
L-ido-Deoxynojirimycin (L-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-L-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a Ki value...
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