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

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

Journal Article · 01 October 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.

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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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Glucose-6-phosphate dehydrogenase deficiency: a historical perspective Beutler, Ernest Blood, Vol. 111, Issue 1 https://doi.org/10.1182/blood-2007-04-077412	journal	January 2008
Early Phagocytosis of Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Erythrocytes Parasitized by Plasmodium falciparum May Explain Malaria Protection in G6PD Deficiency Cappadoro, Marina; Giribaldi, Giuliana; O'Brien, Estella Blood, Vol. 92, Issue 7 https://doi.org/10.1182/blood.v92.7.2527.2527_2527_2534	journal	October 1998
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Efficient Mutagenesis by Cas9 Protein-Mediated Oligonucleotide Insertion and Large-Scale Assessment of Single-Guide RNAs Gagnon, James A.; Valen, Eivind; Thyme, Summer B. PLoS ONE, Vol. 9, Issue 5 https://doi.org/10.1371/journal.pone.0098186	journal	May 2014
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Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency Belfield, Kristen D.; Tichy, Eric M. American Journal of Health-System Pharmacy, Vol. 75, Issue 3 https://doi.org/10.2146/ajhp160961	journal	February 2018
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Improved Erythrocyte Survival with High-Dose Vitamin E in Chronic Hemolyzing G6PD and Glutathione Synthetase Deficiencies Spielberg, S. P. Annals of Internal Medicine, Vol. 90, Issue 1 https://doi.org/10.7326/0003-4819-90-1-53	journal	January 1979
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Scaling and assessment of data quality Evans, Philip Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 1, p. 72-82 https://doi.org/10.1107/S0907444905036693	journal	December 2005
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Origins and implications of neglect of G6PD deficiency and primaquine toxicity in Plasmodium vivax malaria Baird, Kevin Pathogens and Global Health, Vol. 109, Issue 3 https://doi.org/10.1179/2047773215Y.0000000016	journal	May 2015
Glucose-6-phosphate dehydrogenase deficiency: a historical perspective Beutler, Ernest Blood, Vol. 111, Issue 1 https://doi.org/10.1182/blood-2007-04-077412	journal	January 2008
Early Phagocytosis of Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Erythrocytes Parasitized by Plasmodium falciparum May Explain Malaria Protection in G6PD Deficiency Cappadoro, Marina; Giribaldi, Giuliana; O'Brien, Estella Blood, Vol. 92, Issue 7 https://doi.org/10.1182/blood.V92.7.2527	journal	October 1998
Early Phagocytosis of Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Erythrocytes Parasitized by Plasmodium falciparum May Explain Malaria Protection in G6PD Deficiency Cappadoro, Marina; Giribaldi, Giuliana; O'Brien, Estella Blood, Vol. 92, Issue 7 https://doi.org/10.1182/blood.v92.7.2527.2527_2527_2534	journal	October 1998
Particle Simulation of Oxidation Induced Band 3 Clustering in Human Erythrocytes Shimo, Hanae; Arjunan, Satya Nanda Vel; Machiyama, Hiroaki PLOS Computational Biology, Vol. 11, Issue 6 https://doi.org/10.1371/journal.pcbi.1004210	journal	June 2015
Efficient Mutagenesis by Cas9 Protein-Mediated Oligonucleotide Insertion and Large-Scale Assessment of Single-Guide RNAs Gagnon, James A.; Valen, Eivind; Thyme, Summer B. PLoS ONE, Vol. 9, Issue 5 https://doi.org/10.1371/journal.pone.0098186	journal	May 2014
Bilirubin Conjugation, Reflected by Conjugated Bilirubin Fractions, in Glucose-6-Phosphate Dehydrogenase-deficient Neonates: A Determining Factor in the Pathogenesis of Hyperbilirubinemia Kaplan, M.; Muraca, M.; Hammerman, C. PEDIATRICS, Vol. 102, Issue 3 https://doi.org/10.1542/peds.102.3.e37	journal	September 1998
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Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency Belfield, Kristen D.; Tichy, Eric M. American Journal of Health-System Pharmacy, Vol. 75, Issue 3 https://doi.org/10.2146/ajhp160961	journal	February 2018
Glucose-6-Phosphate Dehydrogenase Deficiency and Type 2 Diabetes Heymann, A. D.; Cohen, Y.; Chodick, G. Diabetes Care, Vol. 35, Issue 8 https://doi.org/10.2337/dc11-2527	journal	July 2012
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Glucose-6-phosphate dehydrogenase deficiency and incidence of cataract in Sicily Moro, F.; Gorgone, G.; Volti, S. Li Ophthalmic Paediatrics and Genetics, Vol. 5, Issue 3 https://doi.org/10.3109/13816818509006134	journal	January 1985
Data mining and pathway analysis of glucose-6-phosphate dehydrogenase with natural language processing Chen, Long; Zhang, Chunhua; Wang, Yanling Molecular Medicine Reports, Vol. 16, Issue 2 https://doi.org/10.3892/mmr.2017.6785	journal	February 2017
Detection of Occult Glomerular Dysfunction in Glucose Six Phosphate Dehydrogenase Deficiency Anemia Abdel Hakeem, Gehan; Abdel Naem, Emad; Swelam, Salwa Mediterranean Journal of Hematology and Infectious Diseases, Vol. 8 https://doi.org/10.4084/mjhid.2016.038	journal	December 2015
Improved Erythrocyte Survival with High-Dose Vitamin E in Chronic Hemolyzing G6PD and Glutathione Synthetase Deficiencies Spielberg, S. P. Annals of Internal Medicine, Vol. 90, Issue 1 https://doi.org/10.7326/0003-4819-90-1-53	journal	January 1979

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Discovery of Small-Molecule Activators for Glucose-6-Phosphate Dehydrogenase (G6PD) Using Machine Learning Approaches Saddala, Madhu Sudhana; Lennikov, Anton; Huang, Hu International Journal of Molecular Sciences, Vol. 21, Issue 4 https://doi.org/10.3390/ijms21041523	journal	February 2020
Small‐Molecule Activators of Glucose‐6‐phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface Raub, Andrew G.; Hwang, Sunhee; Horikoshi, Naoki ChemMedChem, Vol. 14, Issue 14 https://doi.org/10.1002/cmdc.201900341	journal	June 2019
Neuroprotection by glucose‐6‐phosphate dehydrogenase and the pentose phosphate pathway Tang, Bor Luen Journal of Cellular Biochemistry, Vol. 120, Issue 9 https://doi.org/10.1002/jcb.29004	journal	April 2019
Discovery of Small-Molecule Activators for Glucose-6-Phosphate Dehydrogenase (G6PD) Using Machine Learning Approaches Saddala, Madhu Sudhana; Lennikov, Anton; Huang, Hu International Journal of Molecular Sciences, Vol. 21, Issue 4 https://doi.org/10.3390/ijms21041523	journal	February 2020

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