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3,4,5-Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers.

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.

SUBMITTER: Vanni C

PROVIDER: S-EPMC9400994 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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3,4,5-Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers.

Vanni Costanza C Clemente Francesca F Paoli Paolo P Morrone Amelia A Matassini Camilla C Goti Andrea A Cardona Francesca F

Chembiochem : a European journal of chemical biology 20220407 11

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 m ...[more]

PMID: 35322924

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