ENTAMOEBA-HISTOLYTICA - COMPUTER-ASSISTED MODELING OF PHOSPHOFRUCTOKINASE FOR THE PREDICTION OF BROAD-SPECTRUM ANTIPARASITIC AGENTS

Pyrophosphate-dependent phosphofructokinase (PPi-PFK) is the rate-limi ting glycolytic enzyme found in the pathogenic protists Entamoeba hist olytica, Giardia lamblia, Toxoplasma gondii, Trichomonas vaginalis, an d Naegleria fowleri. The enzyme differs significantly from ATP-depende nt phosphofructokinases found in humans and as such represents an impo rtant drug target. Current therapy for infections caused by these path ogens is inadequate, especially for children, pregnant women, and the immune compromised, The development of more selective, safer agents is imperative, as parasitic infections are currently a significant healt h threat worldwide and will likely become increasingly common agents o f disease in the future, For the purpose of designing drugs to treat p arasitic infections, we have constructed a model of PPi-PFK from E. hi stolytica based on the three-dimensional structure of the ATP-dependen t PFK from Bacillus stearothermophilus. The model was used with the co mputer program Dock 3.5 (University of California, San Francisco) to p redict the binding of pyrophosphate and selected bisphosphonates to th e enzyme. The predicted drug-enzyme interactions suggested that two of these compounds would be competitive inhibitors of pyrophosphate. The se drugs were tested against E. histolytica and inhibited the growth o f amebae ill vitro. This class of compounds may have broad-spectrum an tiparasitic activity and, in the future, may facilitate the treatment of serious parasitic infections. (C) 1997 Academic, Press.