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Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

ABSTRACT: Clinical investigation of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 resulted in serious adverse neurological events. Structurally unrelated FAAH inhibitors tested in humans have not presented safety concerns, suggesting that BIA 10-2474 has off-target activities. A recent activity-based protein profiling (ABPP) study revealed that BIA 10-2474 and one of its major metabolites inhibit multiple members of the serine hydrolase class to which FAAH belongs. Here, we extend these studies by performing a proteome-wide analysis of covalent targets of BIA 10-2474 metabolites. Using alkynylated probes for click chemistry-ABPP in human cells, we show that des-methylated metabolites of BIA 10-2474 covalently modify the conserved catalytic cysteine in aldehyde dehydrogenases, including ALDH2, which has been implicated in protecting the brain from oxidative stress-related damage. These findings indicate that BIA 10-2474 and its metabolites have the potential to inhibit multiple mechanistically distinct enzyme classes involved in nervous system function.

SUBMITTER: Huang Z

PROVIDER: S-EPMC6383364 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

Huang Zhen Z Ogasawara Daisuke D Seneviratne Uthpala I UI Cognetta Armand B AB Am Ende Christopher W CW Nason Deane M DM Lapham Kimberly K Litchfield John J Johnson Douglas S DS Cravatt Benjamin F BF

ACS chemical biology 20190131 2

Clinical investigation of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 resulted in serious adverse neurological events. Structurally unrelated FAAH inhibitors tested in humans have not presented safety concerns, suggesting that BIA 10-2474 has off-target activities. A recent activity-based protein profiling (ABPP) study revealed that BIA 10-2474 and one of its major metabolites inhibit multiple members of the serine hydrolase class to which FAAH belongs. Here, we extend these stud ...[more]

PMID: 30702848

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Dataset Information

Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

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Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

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