Prism[5]arene Iminosugar Bioconjugates Are Potent Multivalent Inhibitors and Mutation Specific Pharmacological Chaperones of Glucocerebrosidase (GCase) Activity.
4 affiliations
- 1Laboratory of Supramolecular Chemistry, Dipartimento di Chimica e Biologia "A. Zambelli", Università di Salerno, Via Giovanni Paolo II 132, 84084Fisciano, Salerno, Italy.
- 2Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, via della Lastruccia 3-13, 50019Sesto Fiorentino, FI, Italy.
- 3Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children's Hospital, IRCCS, Viale Pieraccini 24, 50139Firenze, Italy.
- 4Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 24, 50139Firenze, Italy.
Abstract
When trihydroxypiperidine (PIP) or DAB-1 pyrrolidine (PYR) iminosugars are multimerized on the prism[5]arene scaffold, they generate highly efficient multivalent inhibitors of GCase. Binding trihydroxypiperidine to the rims of prism[5]arene (PrS[5]PIP) results in a multivalent derivative that is more effective than others reported in the literature with the same bioactive unit. This efficacy is attributed to the role of prism[5]arene, whose barrel-like shape exposes an external π-surface that enables van der Waals contacts and other secondary interactions with the enzyme, thereby enhancing affinity for GCase through dimer stabilization. The high efficiency of PrS[5]PIP is supported by in silico calculations that showed how the crowding of the bioactive units on the rims of the macrocycle promotes a rearrangement allowing the active site to accommodate two trihydroxypiperidine units, which engage in hydrogen bonding with the catalytically active Glu residues. Due to their inhibitory potency, these prismarene derivatives have been tested as pharmacological chaperones in intact cell lines from Gaucher patients carrying different mutations. The results indicated that the PrS[5]PIP is more effective toward the N370S mutation, while the DAB-1 pyrrolidine iminosugar PrS[5]PYR unexpectedly enhances L444P mutant GCase activity. This suggests that the type of iminosugar linked to the prismarene scaffold influences GCase activity rescue in a mutation-dependent manner and opens the way for the future development of increasingly efficient pharmacological chaperones.
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BibTeX
@article{palmieri2026prism5arene,
title = {{Prism[5]arene Iminosugar Bioconjugates Are Potent Multivalent Inhibitors and Mutation Specific Pharmacological Chaperones of Glucocerebrosidase (GCase) Activity.}},
author = {Anna Palmieri and Francesca Clemente and Maria Manuela Ignoto and Fabio Buonsenso and Miriana Attanasio and Margherita De Rosa and Carmen Talotta and Paolo Della Sala and Rocco Del Regno and Veronica Iuliano and Amelia Morrone and Francesca Cardona and Andrea Goti and Camilla Matassini and Carmine Gaeta},
journal = {Bioconjugate chemistry},
year = {2026},
month = sep,
doi = {10.1021/acs.bioconjchem.6c00273},
url = {https://europepmc.org/article/MED/42915455},
note = {CC BY},
}
RIS
TY - JOUR
TI - Prism[5]arene Iminosugar Bioconjugates Are Potent Multivalent Inhibitors and Mutation Specific Pharmacological Chaperones of Glucocerebrosidase (GCase) Activity.
AU - Anna Palmieri
AU - Francesca Clemente
AU - Maria Manuela Ignoto
AU - Fabio Buonsenso
AU - Miriana Attanasio
AU - Margherita De Rosa
AU - Carmen Talotta
AU - Paolo Della Sala
AU - Rocco Del Regno
AU - Veronica Iuliano
AU - Amelia Morrone
AU - Francesca Cardona
AU - Andrea Goti
AU - Camilla Matassini
AU - Carmine Gaeta
PY - 2026
DA - 2026/09/01
JO - Bioconjugate chemistry
DO - 10.1021/acs.bioconjchem.6c00273
UR - https://europepmc.org/article/MED/42915455
AB - When trihydroxypiperidine (PIP) or DAB-1 pyrrolidine (PYR) iminosugars are multimerized on the prism[5]arene scaffold, they generate highly efficient multivalent inhibitors of GCase. Binding trihydroxypiperidine to the rims of prism[5]arene (PrS[5]PIP) results in a multivalent derivative that is more effective than others reported in the literature with the same bioactive unit. This efficacy is attributed to the role of prism[5]arene, whose barrel-like shape exposes an external π-surface that enables van der Waals contacts and other secondary interactions with the enzyme, thereby enhancing affinity for GCase through dimer stabilization. The high efficiency of PrS[5]PIP is supported by in silico calculations that showed how the crowding of the bioactive units on the rims of the macrocycle promotes a rearrangement allowing the active site to accommodate two trihydroxypiperidine units, which engage in hydrogen bonding with the catalytically active Glu residues. Due to their inhibitory potency, these prismarene derivatives have been tested as pharmacological chaperones in intact cell lines from Gaucher patients carrying different mutations. The results indicated that the PrS[5]PIP is more effective toward the N370S mutation, while the DAB-1 pyrrolidine iminosugar PrS[5]PYR unexpectedly enhances L444P mutant GCase activity. This suggests that the type of iminosugar linked to the prismarene scaffold influences GCase activity rescue in a mutation-dependent manner and opens the way for the future development of increasingly efficient pharmacological chaperones.
SN - 1043-1802
SN - 1520-4812
ER -