Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474-Reference-Cited by-同舟云学术

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

Published:2017-06-09 Issue:6342 Volume:356 Page:1084-1087
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

van Esbroeck Annelot C. M.¹^ORCID,Janssen Antonius P. A.¹^ORCID,Cognetta Armand B.²^ORCID,Ogasawara Daisuke²^ORCID,Shpak Guy³^ORCID,van der Kroeg Mark³^ORCID,Kantae Vasudev⁴^ORCID,Baggelaar Marc P.¹^ORCID,de Vrij Femke M. S.³,Deng Hui¹^ORCID,Allarà Marco⁵^ORCID,Fezza Filomena⁶^ORCID,Lin Zhanmin⁷^ORCID,van der Wel Tom¹^ORCID,Soethoudt Marjolein¹^ORCID,Mock Elliot D.¹^ORCID,den Dulk Hans¹^ORCID,Baak Ilse L.¹^ORCID,Florea Bogdan I.⁸,Hendriks Giel⁹^ORCID,De Petrocellis Luciano⁵^ORCID,Overkleeft Herman S.⁸^ORCID,Hankemeier Thomas⁴^ORCID,De Zeeuw Chris I.⁷¹⁰,Di Marzo Vincenzo⁵^ORCID,Maccarrone Mauro¹¹¹²^ORCID,Cravatt Benjamin F.²^ORCID,Kushner Steven A.³^ORCID,van der Stelt Mario¹^ORCID

Affiliation:

1. Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.

2. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.

3. Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands.

4. Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.

5. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy.

6. Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.

7. Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands.

8. Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.

9. Toxys B.V., Robert Boyleweg 4, 2333 CG, Leiden, Netherlands.

10. Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Sciences, 1105 BA, Amsterdam, Netherlands.

11. European Centre for Brain Research–Institute for Research and Healthcare (IRCCS) Santa Lucia Foundation, Via del Fosso del Fiorano 65, 00143 Rome, Italy.

12. Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.

Abstract

A clue to a drug's neurotoxicity? The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered brain damage. As an initial step in investigating whether inhibition of off-target proteins by BIA 10-2474 might contribute to its clinical neurotoxicity, van Esbroeck et al. used activity-based proteomic assays to identify proteins targeted by the drug. Studying human cells and brain samples from subjects not associated with the trial, they found that BIA 10-2474 targeted several different lipases in addition to FAAH. It also substantially altered lipid metabolism in cultured neurons. Science , this issue p. 1084

Funder

National Institutes of Health

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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