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 journalArticlepeer-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 languageEnglish
Pages (from-to)1834-1845
Number of pages12
JournalChemistry - A European Journal
Volume26
Issue number8
DOIs
Publication statusPublished - Feb 6 2020

Keywords

  • aggregation
  • chaperones
  • ER stress
  • lipophilicity
  • protein folding

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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