Targeting Host Glycolysis as a Strategy for Antimalarial Development

Abstract

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.

Synthetic Red Blood Cell-Specific Glycolytic Intermediate 2,3-Diphosphoglycerate (2,3-DPG) Inhibits Plasmodium falciparum Development In Vitro

“…Targeting host glycolysis as an antimalarial strategy is a promising approach and has been attempted in a few studies. Jezewski et al (2021) observed that enolase inhibition increased erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis, also affecting parasite development. However, an inhibitory effect also on parasite enolase was not unequivocally ruled out, so the interaction mechanism was not clearly established.…”

Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers

“…1 H NMR (600 MHz, CDCl 3 ) 8.24 (s, 1H), 5.77 (q, J = 7.8, 5.4, 5.4 Hz, 2H), 5.73 (t, J = 6.7, 7.7 Hz, 2H), 4.94 (m, 2H), 3.65 (m, 2H), 3.17 (dt, J = 27.9 Hz, 1H), 2.25 (m, 1H), 2.15 (m, 2H), 1.92 (m, 1H), 1.31−1.34 (m, 12H). 13…”

“…1 H NMR (500 MHz, CDCl 3 ): δ 9.85 (s, 1H), 4.06−4.27 (m, 4H), 3.31−3.43 (m, 2H), 3.10 (q, J = 7.01 Hz, 4H), 3.04 (dt, J = 26.35 Hz, J = 7.06 Hz, 1H), 1.79−1.90 (m, 1H), 1.70−1.76 (m, 1H), 1.62−1.69 (m, 1H), 1.51−1.58 (m, 1H), 1.17 (s, 18H). 13…”

“…Note: some aliphatic ring protons were hidden under the acetyl ester proton peak at 2.18 ppm; alpha proton was partially hidden under the triplet at 3.13 ppm. 13…”

“…Using PhAH as a starting point, we conducted molecular docking studies to identify derivatives with improved specificity for human ENO2 . Human ENO1 and ENO2 share 84% sequence identitybearing even higher resemblance in the active site. , Maximizing inhibitor specificity for ENO2 was an important design goal to avoid inhibition of erythrocytic ENO1 the sole isoform present in erythrocyteswhich can result in anemia. , With these constraints, we identified a cyclic derivative of PhAH, deoxySF2312 ( 2 ), which bore close resemblance to the natural product antibiotic, SF2312 ( 3 ; PDB: 4ZCW). We clarified the stereochemical requirements for active site binding by SF2312 by synthesizing a Cα-methyl derivative of SF2312 (mSF2312, 4 ; PDB: 5EU9), which showed that ENO2 binding was specific to the 3 S , 5 S enantiomer .…”