Dataset Information

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

ABSTRACT: 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.

SUBMITTER: van Esbroeck ACM

PROVIDER: S-EPMC5641481 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

van Esbroeck Annelot C M ACM Janssen Antonius P A APA Cognetta Armand B AB Ogasawara Daisuke D Shpak Guy G Shpak Guy G van der Kroeg Mark M Kantae Vasudev V Baggelaar Marc P MP de Vrij Femke M S FMS Deng Hui H Allarà Marco M Fezza Filomena F Lin Zhanmin Z van der Wel Tom T Soethoudt Marjolein M Mock Elliot D ED den Dulk Hans H Baak Ilse L IL Florea Bogdan I BI Hendriks Giel G De Petrocellis Luciano L Overkleeft Herman S HS Hankemeier Thomas T De Zeeuw Chris I CI Di Marzo Vincenzo V Maccarrone Mauro M Cravatt Benjamin F BF Kushner Steven A SA van der Stelt Mario M

Science (New York, N.Y.) 20170601 6342

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 B ...[more]

PMID: 28596366

Similar Datasets

Project description:BACKGROUND: Anandamide and 2-arachidonoylglycerol are neuromodulatory lipids interacting with cannabinoid receptors, whose availability is regulated by the balance between 'on demand' generation and enzymatic degradation [by fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase]. Given the reported effects of anandamide on dopamine transmission, we investigated the influence of endocannabinoids and URB597, a well-known FAAH inhibitor, on the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. EXPERIMENTAL APPROACH: We investigated TH expression in N1E115 neuroblastoma using a reporter gene assay, as well as mRNA and protein quantifications. FAAH inhibition was confirmed by measuring radiolabelled substrate hydrolysis and endogenous endocannabinoids. KEY RESULTS: Anandamide decreased TH promoter activity in N1E115 cells through CB? receptor activation. Unexpectedly, URB597 reduced TH expression (pEC?? = 8.7 ± 0.2) through FAAH-independent mechanisms. Indeed, four structurally unrelated inhibitors of FAAH had no influence on TH expression, although all the inhibitors increased endocannabinoid levels. At variance with the endocannabinoid responses, the use of selective antagonists indicated that the URB597-mediated decrease in TH expression was not directed by the CB? receptor, but rather by abnormal-cannabidiol-sensitive receptors and PPARs. Further supporting the physiological relevance of these in vitro data, URB597 administration resulted in reduced TH mRNA levels in mice brain. CONCLUSIONS: While confirming the implication of endocannabinoids on the modulation of TH, we provide strong evidence for additional physiologically relevant off-target effects of URB597. In light of the numerous preclinical studies involving URB597, particularly in anxiety and depression, the existence of non-CB? and non-FAAH mediated influences of URB597 on key enzymes of the catecholaminergic transmission system should be taken into account when interpreting the data.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets