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

被引：11

作者：

Azoulay-Ginsburg, Salome ^{[1
]}

Trobiani, Laura ^{[2
,3
]}

Setini, Andrea ^{[2
,3
]}

Favaloro, Flores Lietta ^{[2
,3
]}

Giorda, Ezio ^{[5
]}

Jacob, Avi ^{[6
]}

Hauschner, Hagit ^{[6
]}

Levy, Laura ^{[1
]}

Cestra, Gianluca ^{[2
,3
,4
]}

De Jaco, Antonella ^{[2
,3
]}

Gruzman, Arie ^{[1
]}

机构：

[1] Bar Ilan Univ, Dept Chem, IL-5290002 Ramat Gan, Israel

[2] Sapienza Univ Rome, Dept Biol & Biotechnol Charles Darwin, Piazzale Aldo Moro 5, I-00185 Rome, Italy

[3] Sapienza Univ Rome, Cenci Bolognetti Fdn, Pasteur Inst, Piazzale Aldo Moro 5, I-00185 Rome, Italy

[4] Sapienza Univ Rome, Natl Res Council, Inst Mol Biol & Pathol, Piazzale Aldo Moro 5, I-00185 Rome, Italy

[5] Osped Pediatr Bambin Gesu Rome, Piazza St Onofrio 4, I-00165 Rome, Italy

[6] Bar Ilan Univ, Fac Life Sci, IL-5290002 Ramat Gan, Israel

来源：

CHEMISTRY-A EUROPEAN JOURNAL | 2020年 / 26卷 / 08期

关键词：

aggregation; chaperones; ER stress; lipophilicity; protein folding; MOLECULAR-GENETIC BASIS; CHEMICAL CHAPERONES; UNFOLDED PROTEIN; R451C MUTATION; CELL-DEATH; MECHANISM; STRESS; BSA;

D O I：

10.1002/chem.201904292

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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).

引用

页码：1834 / 1845

页数：12

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