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

Salome Azoulay-Ginsburg; Laura Trobiani; Andrea Setini; Flores Lietta Favaloro; Ezio Giorda; Avi Jacob; Hagit Hauschner; Laura Levy; Gianluca Cestra; Antonella De Jaco; Arie Gruzman

doi:10.1002/chem.201904292

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

Salome Azoulay-Ginsburg, Laura Trobiani, Andrea Setini, Flores Lietta Favaloro, Ezio Giorda, Avi Jacob, Hagit Hauschner, Laura Levy, Gianluca Cestra, Antonella De Jaco, Arie Gruzman

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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).

Original language	English
Pages (from-to)	1834-1845
Number of pages	12
Journal	Chemistry - A European Journal
Volume	26
Issue number	8
DOIs	https://doi.org/10.1002/chem.201904292
State	Published - 6 Feb 2020

Bibliographical note

Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Funding

We thank Steve Manch for the English editing of the article. We thank the Israel Ministry of Science, Technology, and Space, along with the Italian Ministry of Foreign Affairs and the International Cooperation, the Directorate General for Country Promotion (Unit for Scientific and Technological Cooperation) for collaboration grant number 3-13325, which was awarded to A.G. and G.C. The Germany Israel Foundation (GIF) partially supported this work (Grant no. I-1410-201.9/2017) for A.G. In addition, S.A.-G. thanks NAAMAT, for the Edelson Foundation prize for outstanding women researchers in the field of chemistry and pharmacology and for the Navon fellowship for Ph.D. students, awarded by the Israel Ministry of Science, Technology and Space. We thank Steve Manch for the English editing of the article. We thank the Israel Ministry of Science, Technology, and Space, along with the Italian Ministry of Foreign Affairs and the International Cooperation, the Directorate General for Country Promotion (Unit for Scientific and Technological Cooperation) for collaboration grant number 3‐13325, which was awarded to A.G. and G.C. The Germany Israel Foundation (GIF) partially supported this work (Grant no. I‐1410‐201.9/2017) for A.G. In addition, S.A.‐G. thanks NAAMAT, for the Edelson Foundation prize for outstanding women researchers in the field of chemistry and pharmacology and for the Navon fellowship for Ph.D. students, awarded by the Israel Ministry of Science, Technology and Space.

Funders	Funder number
Edelson Foundation
Germany Israel Foundation	I‐1410‐201.9/2017
Israel Ministry of Science, Technology, and Space
Ministry of Science, Technology and Space
Ministry for Foreign Affairs	3‐13325
Ministry of science and technology, Israel
Ministero degli Affari Esteri e della Cooperazione Internazionale

Keywords

ER stress
aggregation
chaperones
lipophilicity
protein folding

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10.1002/chem.201904292

Cite this

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title = "A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins",

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).",

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doi = "10.1002/chem.201904292",

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AU - Favaloro, Flores Lietta

AU - Giorda, Ezio

AU - Jacob, Avi

AU - Hauschner, Hagit

AU - Levy, Laura

AU - Cestra, Gianluca

AU - De Jaco, Antonella

AU - Gruzman, Arie

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AB - 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).

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

Abstract

Bibliographical note

Funding

Keywords

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Flow Cytometry

Cite this

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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Equipment

Flow Cytometry

Cite this