Phenylboronic acids as pH-selective ligands for arylsulfatase B: a lead for pharmacological chaperones against Maroteaux–Lamy syndrome

Loss of function in lysosomal arylsulfatase B (ARSB) leads to Maroteaux–Lamy syndrome, a form of the mucopolysaccharidoses. Mutations in ARSB, at least those characterized in detail, often destabilize and interfere with the folding of the ARSB protein, resulting in the loss of functional ARSB in lysosomes. Pharmacological chaperones, which are ligands that assist in protein folding by binding to folding intermediates in the endoplasmic reticulum, are proposed to be potential drug candidates for such protein misfolding diseases. However, small-molecule ligands for ARSB have not been widely studied and most of the known ligands are sulfate compounds, which are highly polar and do not readily cross the membrane. Since pharmacological chaperones must be able to enter the cell and the endoplasmic reticulum, a surrogate pharmacophore with membrane permeable properties is needed. In this study, we identified phenylboronic acid as an effective sulfate surrogate with membrane permeability, via competitive enzymatic assay against ARSB. Additionally, phenylboronic acids were more potent at neutral pH and less so at acidic pH, exhibiting a pH selective activity profile ideal for pharmacological chaperones. Subsequent structure-activity relationship studies identified more potent derivatives, and ARSB was protected from thermal denaturation in the presence of the derivatives, supporting direct binding of the phenylboronic acids. Although further studies will be required to determine if these phenylboronic acids could act as pharmacological chaperones for ARSB mutants, our finding of phenylboronic acid as a pH-selective surrogate pharmacophore for the aryl sulfate should be valuable for designing pharmacological chaperones for sulfatases in the future.