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

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

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

Afiliação

Azoulay-Ginsburg S; Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
Trobiani L; Department of Biology and Biotechnology "Charles Darwin", and, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy.
Setini A; Department of Biology and Biotechnology "Charles Darwin", and, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy.
Favaloro FL; Department of Biology and Biotechnology "Charles Darwin", and, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy.
Giorda E; Ospedale Pediatrico Bambin Gesù-Rome, Piazza di Sant'Onofrio 4, Rome, 00165, Italy.
Jacob A; Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
Hauschner H; Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
Levy L; Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
Cestra G; Department of Biology and Biotechnology "Charles Darwin", and, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy.
De Jaco A; Institute of Molecular Biology and Pathology-National Research Council, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy.
Gruzman A; Department of Biology and Biotechnology "Charles Darwin", and, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy.

Chemistry ; 26(8): 1834-1845, 2020 Feb 06.

Article em En | MEDLINE | ID: mdl-31773792

ABSTRACT

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, compoundâ5 reduced the secretion rate of autism-linked Arg451Cys Neuroligin3 (R451C NLGN3).

Assuntos

Fenilbutiratos/química; Proteínas/química; Animais; Moléculas de Adesão Celular Neuronais/química; Moléculas de Adesão Celular Neuronais/genética; Moléculas de Adesão Celular Neuronais/metabolismo; Sobrevivência Celular/efeitos dos fármacos; Células HEK293; Humanos; Proteínas de Membrana/química; Proteínas de Membrana/genética; Proteínas de Membrana/metabolismo; Mutagênese Sítio-Dirigida; Proteínas do Tecido Nervoso/química; Proteínas do Tecido Nervoso/genética; Proteínas do Tecido Nervoso/metabolismo; Células PC12; Fenilbutiratos/farmacologia; Agregados Proteicos/efeitos dos fármacos; Dobramento de Proteína; Proteínas/metabolismo; Ratos

Palavras-chave

ER stress; aggregation; chaperones; lipophilicity; protein folding

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilbutiratos / Proteínas Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

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