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.

3,4,5-Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers / Costanza Vanni, Francesca Clemente, Paolo Paoli, Amelia Morrone, Camilla Matassini, Andrea Goti, Francesca Cardona. - In: CHEMBIOCHEM. - ISSN 1439-7633. - STAMPA. - 23:(2022), pp. 1-8. [10.1002/cbic.202200077]

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

Costanza Vanni
Membro del Collaboration Group
;
Francesca Clemente
Membro del Collaboration Group
;
Paolo Paoli
Membro del Collaboration Group
;
Amelia Morrone
Membro del Collaboration Group
;
Camilla Matassini
Conceptualization
;
Andrea Goti
Membro del Collaboration Group
;
Francesca Cardona
Conceptualization
2022

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.
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Costanza Vanni, Francesca Clemente, Paolo Paoli, Amelia Morrone, Camilla Matassini, Andrea Goti, Francesca Cardona
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1266893
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