Pyrophosphate-dependent phosphofructokinase (
PPi-PFK) is the rate-limiting glycolytic
enzyme found in the pathogenic protists Entamoeba histolytica, Giardia lamblia, Toxoplasma gondii, Trichomonas vaginalis, and Naegleria fowleri. The
enzyme differs significantly from
ATP-dependent
phosphofructokinases found in humans and as such represents an important
drug target. Current
therapy for
infections caused by these pathogens is inadequate, especially for children, pregnant women, and the immune compromised. The development of more selective, safer agents in imperative, as
parasitic infections are currently a significant health threat worldwide and will likely become increasingly common agents of disease in the future. For the purpose of designing drugs to treat
parasitic infections, we have constructed a model of
PPi-PFK from E. histolytica based on the three-dimensional structure of the
ATP-dependent PFK from Bacillus stearothermophilus. The model was used with the computer program Dock 3.5 (University of California, San Francisco) to predict the binding of
pyrophosphate and selected
bisphosphonates to the
enzyme. The predicted
drug-
enzyme interactions suggested that two of these compounds would be competitive inhibitors of
pyrophosphate. These drugs were tested against E. histolytica and inhibited the growth of amebae in vitro. This class of compounds may have broad-spectrum
antiparasitic activity and, in the future, may facilitate the treatment of serious
parasitic infections.