TY - JOUR
T1 - Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG
AU - Iyer, Sangeetha
AU - Sam, Feba S.
AU - DiPrimio, Nina
AU - Preston, Graeme
AU - Verheijen, Jan
AU - Murthy, Kausalya
AU - Parton, Zachary
AU - Tsang, Hillary
AU - Lao, Jessica
AU - Morava, Eva
AU - Perlstein, Ethan O.
N1 - Funding Information:
We acknowledge Maggie’s PMM2-CDG Cure, LLC as a primary funding source. This work was also supported by the National Institutes of Health [1 U54 NS115198-0 to E.M.].
Publisher Copyright:
© 2019. Published by The Company of Biologists Ltd.
PY - 2019
Y1 - 2019
N2 - Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the wormbased phenotypic screen, 12 were plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.We demonstrate that epalrestat is the first small molecule activator ofPMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.
AB - Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the wormbased phenotypic screen, 12 were plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.We demonstrate that epalrestat is the first small molecule activator ofPMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.
KW - Aldose reductase inhibitor
KW - Congenital disorder of glycosylation
KW - Drug repurposing
KW - Epalrestat
KW - PMM2-CDG
KW - Phosphomannomutase 2 deficiency
UR - http://www.scopus.com/inward/record.url?scp=85074962708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074962708&partnerID=8YFLogxK
U2 - 10.1242/dmm.040584
DO - 10.1242/dmm.040584
M3 - Article
C2 - 31636082
AN - SCOPUS:85074962708
SN - 1754-8403
VL - 12
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
IS - 11
M1 - dmm.040584
ER -