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

Hwang, Sunhee; Mruk, Karen; Rahighi, Simin; Raub, Andrew G.; Chen, Che -Hong; Dorn, Lisa E.; Horikoshi, Naoki; Wakatsuki, Soichi; Chen, James K.; Mochly-Rosen, Daria

doi:10.1038/s41467-018-06447-z

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

Journal Article · Tue Oct 02 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-06447-z· OSTI ID:1490641

^[1]; ^[1]; Rahighi, Simin ^[2]; Raub, Andrew G. ^[1]; Chen, Che -Hong ^[1]; ^[3]; Horikoshi, Naoki ^[1]; Wakatsuki, Soichi ^[1]; ^[1]; ^[1]

Stanford Univ., Stanford, CA (United States)
Stanford Univ., Stanford, CA (United States); Chapman Univ., Irvine, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Stanford Univ., Stanford, CA (United States); The Ohio State Univ., Columbus, OH (United States); Univ. of Wyoming School of Pharmacy, Laramie, WY (United States)

Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1490641

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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