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

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.

Small‐Molecule Activators of Glucose‐6‐phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface

“…[16,17] Encouraged by the discovery of Alda-1, we set out to identify small molecules that enhance the activity of pathogenicm utants of G6PD. [19] First, we found that analogues (e.g., 3,S cheme 1) prepared using the pharmacophore of the structure provided by the vendor( 1)w ere inactive. [18] As mall-molecule activatoro fs everalp athogenic forms of G6PD (AG1 (2), Scheme 1) was identified from the screen, and ad etailed mechanistic understanding of AG1 was required to further our translational objectives.…”

Geographical Accessibility to Glucose-6-Phosphate Dioxygenase Deficiency Point-of-Care Testing for Antenatal Care in Ghana

“…Furthermore, implementing G6PD deficiency screening tests at PHC clinics will help improve Ghana's malaria control program as well as contribute to Ghana's quest to attain universal health coverage. Moreover, the ability of health providers in resource-limited settings to test the G6PD deficiency status of pregnant women potentially can help them report promptly hemolytic anemia cases caused by G6PD deficiency may during pregnancy management to prevent hematological and several possible serious obstetrical complications such as fetus malformations, infertility, bilirubin-induced neurological damage in newborns, and death [6,40]. In view of these, we recommend a wider implementation of appropriate diagnostic tests for G6PD deficiency testing in rural and resource-limited settings health facilities to improve G6PD deficiency status testing of pregnant women and patients prior to the administration of SP and other antimalaria medicines as well as, facilitate the malaria control/elimination programs with primaquine in malaria-endemic countries.…”

“…This implies that the health facility-to-population ratio for G6PD deficiency POC testing in UER was approximately 1:159,210 (8/1,273,677) population, whilst the health facility-to-women of reproductive age (WORA) was about 1:38,210 (8/305683). Of these eight hospitals, six (6) were District Hospitals owned and managed by the GHS, one (1) owned by a Church (a member of the CHAG), and one (1) Regional Hospital. Of the thirteen administrative districts in the region, five districts (Binduri, Nabdam, Garu-Tempane, Pusiga, and Builsa South) had no health facility providing G6PD deficiency POC testing, as shown in Figure 1.…”

“…The magnitude and geographical (global, regional, and country-level) heterogeneity of G6PD deficiency prevalence rates have public health implications, especially in malaria control or elimination programs involving the administration of antimalarial medicines for most malaria-endemic countries such as Ghana. G6PD deficient individuals are at high risk of severe hemolysis when given anti-malarial drugs such as primaquine, quinine, other sulphonamide-containing medicines [6][7][8], and chloroquine which has been shown to be potent for the treatment of coronavirus disease (COVID-19) [6,9,10], These drugs may cause an irreversible oxidative activity of the body's metabolites on erythrocytes [7,8].…”

Neuroprotection by glucose‐6‐phosphate dehydrogenase and the pentose phosphate pathway

“…Overexpression of G6PD extended lifespan of transgenic HD fly significantly 99 Drosophila transgenic model Overexpression of G6PD in Drosophila neurons delayed proteostasis decline with age and extend lifespan 21 Transgenic mice with moderate expression of G6PD Moderate transgenic overexpression of G6PD in mice extended healthspan and median lifespan of females 24 Development of a G6PD agonist G6PD agonist AG1 effectively activated G6PD and reduced oxidative stress in G6PD-deficient human fibroblasts and zebrafish embryo 22 Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; OGD, oxygen-glucose deprivation; PPP, pentose phosphate pathway. TANG | 14291…”