3, 4, 5‐Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers. (7th April 2022) - Vanni, Costanza
Abstract: The synthesis of five new multivalent derivatives of a trihydroxypiperidine iminosugar was accomplished through copper catalyzed alkyne‐azide cycloaddition (CuAAC) reaction of an azido ending piperidine and several propargylated scaffolds. The resulting multivalent architectures were assayed as inhibitors of lysosomal GCase, the defective enzyme in Gaucher disease. The multivalent compounds resulted in much more potent inhibitors than a parent monovalent reference compound, thus showing a good multivalent effect. Biological investigation of these compounds as pharmacological chaperones revealed that the trivalent derivative (12 ) gives a 2‐fold recovery of the GCase activity on Gaucher patient fibroblasts bearing the L444P/L444P mutations responsible for neuropathies. Additionally, a thermal denaturation experiment showed its ability to impart stability to the recombinant enzyme used in therapy. Abstract : The multivalent piperidine iminosugars described in this work are strong inhibitors of glucocerebrosidase (GCase), the defective enzyme in Gaucher disease. The trivalent derivative 12 was able to double GCase activity in patient's fibroblasts homozygous for the L444P mutation, which is resistant to most pharmacological chaperones. Co‐incubation of 12 with recombinant GCase enzyme paves the way to its application in PC/ERT therapy.