Clioquinol improves catalytic activity of PHGDH and shows antiseizure efficacy in patients

Drug-resistant epilepsy (DRE) affects over 25 million people worldwide and is associated with neuroinflammation. We identified haloquinolines from a drug repurposing library as potent activators of phosphoglycerate dehydrogenase (PHGDH) enzyme, which converts 3-phosphoglycerate to generate serine and the neurotransmitter glycine, and steers anti-inflammatory responses. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5-fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH-dependent antiseizure activity as well as anti-inflammatory properties in vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add-on treatment in severe DRE patients. Therefore, increasing activity of PHGDH is a promising new approach to treat DRE.