Chemical chaperones prevent protein aggregation. However, the use of chemical chaperones as drugs against diseases due to protein aggregation is limited by the very high active concentrations (mm range) required to mediate their effect. One of the most common chemical chaperones is 4-phenylbutyric acid (4-PBA). Despite its unfavorable pharmacokinetic properties, 4-PBA was approved as a drug to treat ornithine cycle diseases. Here, we report that 2-isopropyl-4-phenylbutanoic acid (5) has been found to be 2–10-fold more effective than 4-PBA in several in vitro models of protein aggregation. Importantly, compound 5 reduced the secretion rate of autism-linked Arg451Cys Neuroligin3 (R451C NLGN3).

A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins / Azoulay-Ginsburg, S.; Trobiani, L.; Setini, A.; Favaloro, F. L.; Giorda, E.; Jacob, A.; Hauschner, H.; Levy, L.; Cestra, G.; De Jaco, A.; Gruzman, A.. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 26:8(2020), pp. 1834-1845. [10.1002/chem.201904292]

A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

Trobiani L.
Membro del Collaboration Group
;
Setini A.
Membro del Collaboration Group
;
Favaloro F. L.
Membro del Collaboration Group
;
Cestra G.
Membro del Collaboration Group
;
De Jaco A.
Supervision
;
2020

Abstract

Chemical chaperones prevent protein aggregation. However, the use of chemical chaperones as drugs against diseases due to protein aggregation is limited by the very high active concentrations (mm range) required to mediate their effect. One of the most common chemical chaperones is 4-phenylbutyric acid (4-PBA). Despite its unfavorable pharmacokinetic properties, 4-PBA was approved as a drug to treat ornithine cycle diseases. Here, we report that 2-isopropyl-4-phenylbutanoic acid (5) has been found to be 2–10-fold more effective than 4-PBA in several in vitro models of protein aggregation. Importantly, compound 5 reduced the secretion rate of autism-linked Arg451Cys Neuroligin3 (R451C NLGN3).
2020
aggregation; chaperones; ER stress; lipophilicity; protein folding; animals; cell adhesion molecules, neuronal; cell survival; HEK293 cells; humans; membrane proteins; mutagenesis, site-directed; nerve tissue proteins; PC12 cells; phenylbutyrates; protein aggregates; protein folding; proteins; rats
01 Pubblicazione su rivista::01a Articolo in rivista
A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins / Azoulay-Ginsburg, S.; Trobiani, L.; Setini, A.; Favaloro, F. L.; Giorda, E.; Jacob, A.; Hauschner, H.; Levy, L.; Cestra, G.; De Jaco, A.; Gruzman, A.. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 26:8(2020), pp. 1834-1845. [10.1002/chem.201904292]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1384206
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