A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins.,Chemistry - A European Journal

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A Lipophilic 4-Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins.
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2020-01-27 , DOI: 10.1002/chem.201904292
Salome Azoulay-Ginsburg ₁ , Laura Trobiani ₂ , Andrea Setini ₂ , Flores Lietta Favaloro ₂ , Ezio Giorda ₃ , Avi Jacob ₄ , Hagit Hauschner ₄ , Laura Levy ₁ , Gianluca Cestra _{2,

5} , Antonella De Jaco ₂ , Arie Gruzman ₁

Affiliation

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).

中文翻译：

亲脂性的4-苯基丁酸衍生物，可防止错误折叠的蛋白质聚集和保留。

化学伴侣可以防止蛋白质聚集。但是，化学伴侣蛋白作为抗蛋白质聚集疾病的药物的使用受到介导其作用所需的非常高的活性浓度（毫米范围）的限制。最常见的化学分子伴侣之一是4-苯基丁酸（4-PBA）。尽管其不利的药代动力学特性，但4-PBA被批准用作治疗鸟氨酸周期疾病的药物。在这里，我们报道在一些蛋白质聚集体外模型中，发现2-异丙基-4-苯基丁酸（5）比4-PBA有效2-10倍。重要的是，化合物5降低了自闭症相关的Arg451Cys Neuroligin3（R451C NLGN3）的分泌率。

更新日期：2020-01-27

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