Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator

Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen and Daria Mochly-Rosen ()
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Sunhee Hwang: Stanford University School of Medicine
Karen Mruk: Stanford University School of Medicine
Simin Rahighi: Stanford University School of Medicine
Andrew G. Raub: Stanford University School of Medicine
Che-Hong Chen: Stanford University School of Medicine
Lisa E. Dorn: Stanford University School of Medicine
Naoki Horikoshi: Stanford University School of Medicine
Soichi Wakatsuki: Stanford University School of Medicine
James K. Chen: Stanford University School of Medicine
Daria Mochly-Rosen: Stanford University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency.

Date: 2018
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DOI: 10.1038/s41467-018-06447-z

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