Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.

Autor: van Esbroeck ACM; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Janssen APA; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Cognetta AB 3rd; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA., Ogasawara D; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA., Shpak G; Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands., van der Kroeg M; Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands., Kantae V; Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Baggelaar MP; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., de Vrij FMS; Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands., Deng H; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Allarà M; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy., Fezza F; Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy., Lin Z; Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands., van der Wel T; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Soethoudt M; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Mock ED; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., den Dulk H; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Baak IL; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Florea BI; Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Hendriks G; Toxys B.V., Robert Boyleweg 4, 2333 CG, Leiden, Netherlands., De Petrocellis L; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy., Overkleeft HS; Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., Hankemeier T; Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands., De Zeeuw CI; Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands.; Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Sciences, 1105 BA, Amsterdam, Netherlands., Di Marzo V; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy., Maccarrone M; European Centre for Brain Research-Institute for Research and Healthcare (IRCCS) Santa Lucia Foundation, Via del Fosso del Fiorano 65, 00143 Rome, Italy.; Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy., Cravatt BF; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA., Kushner SA; Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands. m.van.der.stelt@chem.leidenuniv.nl s.kushner@erasmusmc.nl., van der Stelt M; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. m.van.der.stelt@chem.leidenuniv.nl s.kushner@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2017 Jun 09; Vol. 356 (6342), pp. 1084-1087.
DOI: 10.1126/science.aaf7497
Abstrakt: A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.
(Copyright © 2017, American Association for the Advancement of Science.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje