van Esbroeck Annelot C M, Janssen Antonius P A, Cognetta Armand B, Ogasawara Daisuke, Shpak Guy, van der Kroeg Mark, Kantae Vasudev, Baggelaar Marc P, de Vrij Femke M S, Deng Hui, Allarà Marco, Fezza Filomena, Lin Zhanmin, van der Wel Tom, Soethoudt Marjolein, Mock Elliot D, den Dulk Hans, Baak Ilse L, Florea Bogdan I, Hendriks Giel, De Petrocellis Luciano, Overkleeft Herman S, Hankemeier Thomas, De Zeeuw Chris I, Di Marzo Vincenzo, Maccarrone Mauro, Cravatt Benjamin F, Kushner Steven A, van der Stelt Mario
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 2017 Jun 9;356(6342):1084-1087. doi: 10.1126/science.aaf7497.
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.
近期一项针对脂肪酸酰胺水解酶（FAAH）抑制剂BIA 10 - 2474的1期试验导致一名志愿者死亡，并使另外四名志愿者出现了从轻度到重度的神经症状。尽管临床神经毒性的原因尚不清楚，但鉴于其他受试FAAH抑制剂的临床安全性概况，据推测BIA 10 - 2474的脱靶活性可能起到了一定作用。在此，我们使用基于活性的蛋白质组学方法来确定BIA 10 - 2474在人类细胞和组织中的蛋白质相互作用图谱。该分析表明，该药物抑制了几种脂肪酶，而这些脂肪酶并非高选择性且经过临床测试的FAAH抑制剂PF04457845的作用靶点。BIA 10 - 2474而非PF04457845在人类皮质神经元中引起了脂质网络的显著改变，这表明非特异性脂肪酶抑制剂有可能导致神经系统的代谢失调。
