Design of multivalent pharmacological chaperones against Pompe disease via metal-free ligation

We report herein the design of multivalent pharmacological chaperones (PCs), based on D- and L-deoxynojirimycin (DNJ), to treat Pompe disease (PD), a lysosomal storage disorder caused by mutations in the acid alpha-glucosidase (GAA) enzyme. Multivalent DNJ platforms were built on a pentaerythritol core by Copper Azide-Alkyne Click (CuAAC) ligation. Moreover, new phosphorus-containing dendrimers were decorated with DNJ by Strain Promoted Azide-Alkyne Click (SPAAC) reaction. Our main objective was to systematically study how the chirality and the hydrophobicity of these constructs could modulate their ability to inhibit, stabilize, and restore GAA activity. Thermal stabilization assays identified several highly effective stabilizers. Most importantly, the phosphorus-containing dendrimer 15b, an L-N-undecanyl-DNJ derivative, was found to enhance GAA activity by 1.2 fold in fibroblasts from a Pompe patient at the dose of only 0.5 nM. This finding is a significant breakthrough as it represents the first report of a multivalent compound increasing GAA activity in patient cells. This novel multivalent PC, which is a very weak GAA inhibitor, offers a promising avenue for the development of effective treatments for Pompe disease.