The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In the malaria parasite Plasmodium falciparum the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phospho-gluconolactonase (PfGluPho) catalyses the first two steps of the PPP. Since Plasmodium falciparum cells and infected host red blood cells rely on accelerated glucose flux they are dependent on G6PD activity of PfGluPho. The parasite enzyme is essential for Plasmodium proliferation and propagation and it differs structurally and mechanistically from the human orthologs. Thus, PfGluPho fulfills the requirements for being a potential novel target for antimalarial drug design.
This project sought to identify selective inhibitors of the G6PD activity of PfGluPho (PfG6PDH). This Center Probe Report describes the screen and structure activity relationship (SAR) elucidation that led to identification of the first described PfG6PDH inhibitor (889 nM IC50) that was completely selective vs. the human ortholog.