pH-Responsive Trihydroxylated Piperidines Rescue The Glucocerebrosidase Activity in Human Fibroblasts Bearing The Neuronopathic Gaucher-Related L444P/L444P Mutations in GBA1 Gene
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pH-Responsive Trihydroxylated Piperidines Rescue The Glucocerebrosidase Activity in Human Fibroblasts Bearing The Neuronopathic Gaucher-Related L444P/L444P Mutations in GBA1 Gene. / Davighi, Maria Giulia; Matassini, Camilla; Clemente, Francesca; Paoli, Paolo; Morrone, Amelia; Cacciarini, Martina; Goti, Andrea; Cardona, Francesca.
In: ChemBioChem, Vol. 25, No. 1, e202300730, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - pH-Responsive Trihydroxylated Piperidines Rescue The Glucocerebrosidase Activity in Human Fibroblasts Bearing The Neuronopathic Gaucher-Related L444P/L444P Mutations in GBA1 Gene
AU - Davighi, Maria Giulia
AU - Matassini, Camilla
AU - Clemente, Francesca
AU - Paoli, Paolo
AU - Morrone, Amelia
AU - Cacciarini, Martina
AU - Goti, Andrea
AU - Cardona, Francesca
N1 - Publisher Copyright: © 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.
PY - 2024
Y1 - 2024
N2 - Engineering bioactive iminosugars with pH-responsive groups is an emerging approach to develop pharmacological chaperones (PCs) able to improve lysosomal trafficking and enzymatic activity rescue of mutated enzymes. The use of inexpensive l-malic acid allowed introduction of orthoester units into the lipophilic chain of an enantiomerically pure iminosugar affording only two diastereoisomers contrary to previous related studies. The iminosugar was prepared stereoselectively from the chiral pool (d-mannose) and chosen as the lead bioactive compound, to develop novel candidates for restoring the lysosomal enzyme glucocerebrosidase (GCase) activity. The stability of orthoester-appended iminosugars was studied by 1H NMR spectroscopy both in neutral and acidic environments, and the loss of inhibitory activity with time in acid medium was demonstrated on cell lysates. Moreover, the ability to rescue GCase activity in the lysosomes as the result of a chaperoning effect was explored. A remarkable pharmacological chaperone activity was measured in fibroblasts hosting the homozygous L444P/L444P mutation, a cell line resistant to most PCs, besides the more commonly responding N370S mutation.
AB - Engineering bioactive iminosugars with pH-responsive groups is an emerging approach to develop pharmacological chaperones (PCs) able to improve lysosomal trafficking and enzymatic activity rescue of mutated enzymes. The use of inexpensive l-malic acid allowed introduction of orthoester units into the lipophilic chain of an enantiomerically pure iminosugar affording only two diastereoisomers contrary to previous related studies. The iminosugar was prepared stereoselectively from the chiral pool (d-mannose) and chosen as the lead bioactive compound, to develop novel candidates for restoring the lysosomal enzyme glucocerebrosidase (GCase) activity. The stability of orthoester-appended iminosugars was studied by 1H NMR spectroscopy both in neutral and acidic environments, and the loss of inhibitory activity with time in acid medium was demonstrated on cell lysates. Moreover, the ability to rescue GCase activity in the lysosomes as the result of a chaperoning effect was explored. A remarkable pharmacological chaperone activity was measured in fibroblasts hosting the homozygous L444P/L444P mutation, a cell line resistant to most PCs, besides the more commonly responding N370S mutation.
KW - glycomimetic
KW - iminosugar
KW - inhibitor
KW - pH-responsive
KW - pharmacological chaperones
U2 - 10.1002/cbic.202300730
DO - 10.1002/cbic.202300730
M3 - Journal article
C2 - 37877519
AN - SCOPUS:85176956194
VL - 25
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 1
M1 - e202300730
ER -
ID: 374454338