Exploring Multivalent Architectures for Binding and Stabilization of N-Acetylgalactosamine 6-Sufatase

Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, Enzyme re-placement therapy (ERT) is used to treat Morquio A through the infusion of the recombi-nant enzyme VIMIZIM (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of human recombinant GALNS (hrGALNS) with a pharmacologi-cal chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the cop-per(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendri-meric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines and pyrrolizidines) or simple azido ending carbohy-drates as bioactive units. The biological evaluation identified pyrrolidine-based no-navalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC50 in the micromolar range and to act as enzyme stabilizers towards hrGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy.