RT Journal Article
SR Electronic
T1 Targeting host glycolysis as a strategy for antimalarial development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.09.331728
DO 10.1101/2020.10.09.331728
A1 Andrew J. Jezewski
A1 Yu-Hsi Lin
A1 Julie A. Reisz
A1 Rachel Culp-Hill
A1 Yasaman Barekatain
A1 Victoria C. Yan
A1 Angelo D’Alessandro
A1 Florian L. Muller
A1 Audrey R. Odom John
YR 2021
UL http://biorxiv.org/content/early/2021/04/06/2020.10.09.331728.abstract
AB Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase – a critical enzyme in glycolysis – and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of Plasmodium falciparum malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity in malaria parasite growth.Competing Interest StatementThe authors have declared no competing interest.