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

Bar-Ilan University

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

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

Keywords

ER stress
aggregation
chaperones
lipophilicity
protein folding

All Science Journal Classification (ASJC) codes

Catalysis
Organic Chemistry

Access to Document

10.1002/chem.201904292

Cite this

@article{b5854bd8262c4bee97005a25057d7711,

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).",

keywords = "ER stress, aggregation, chaperones, lipophilicity, protein folding",

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

note = "Publisher Copyright: {\textcopyright} 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

year = "2020",

month = feb,

day = "6",

doi = "10.1002/chem.201904292",

language = "الإنجليزيّة",

volume = "26",

pages = "1834--1845",

journal = "Chemistry - A European Journal",

issn = "0947-6539",

publisher = "Wiley-VCH Verlag",

number = "8",

}

TY - JOUR

T1 - A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

AU - Azoulay-Ginsburg, Salome

AU - Trobiani, Laura

AU - Setini, Andrea

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

PY - 2020/2/6

Y1 - 2020/2/6

N2 - 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).

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).

KW - ER stress

KW - aggregation

KW - chaperones

KW - lipophilicity

KW - protein folding

UR - http://www.scopus.com/inward/record.url?scp=85078680238&partnerID=8YFLogxK

U2 - 10.1002/chem.201904292

DO - 10.1002/chem.201904292

M3 - مقالة

C2 - 31773792

SN - 0947-6539

VL - 26

SP - 1834

EP - 1845

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 8

ER -

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

Abstract

Keywords

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this