Some phosphonic acid analogs as inhibitors of pyrophosphate-dependent phosphofructokinase, a novel target in Toxoplasma gondii.
Pyrophosphate-dependent phosphofructokinase (PPi-PFK) was identified previously in Toxoplasma gondii as the only kinase that phosphorylates fructose-6-P to fructose-1,6-bisP. Since such an enzyme is not present in mammals, it was considered to be a good target for prospective selective inhibitors of the parasite. We have examined the effects of several phosphonic acid derivatives, analogs of pyrophosphate, on PPi-PFK activity, as well as on the replication of T. gondii in human foreskin fibroblast (HFF) cells. The most active compound in inhibiting PPi-PFK was tetrasodium carbonyldiphosphonate. Several bisphosphonates and related arylhydrazones showed inhibition of the enzyme, but with higher IC50 values. Although several phosphonoacetic acid derivatives also inhibited PPi-PFK, as a group they were less potent than the bisphosphonate derivatives. Comparison among the structures of various inhibitors and their effects against PPi-PFK indicates that a carbonyl (C=O) or amino (C=N) group between two phosphoryl moieties is associated with more potent enzyme inhibiton. Tetrasodium carbonyldiphosphonate did not show a significant effect against replication of T. gondii cells, probably because, as a charged molecule, it could not cross the cell membrane to reach the intracellular parasite. Tetraisopropyl carbonyldiphosphonate 2,4-dinitrophenylhydrazone showed some selective inhibitory effect against replication of the parasite in the HFF cells and protected the mammalian cells from damage by T. gondii. The results indicate that carbonyldiphosphonic acid is a good prototype compound that is amenable to chemical manipulation, which, in turn, may optimize selective inhibition of T. gondii PPi-PFK and increase accessibility to the intracellular parasite.
Department of Molecular Pharmacology, Stanford University School of Medicine, CA 94305-5332.
Z Y
ZY
Peng
J M
JM
Mansour
F
F
Araujo
J Y
JY
Ju
C E
CE
McKenna
T E
TE
Mansour
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D007659:Ketones / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology; D063065:Organophosphonates / Q000494:pharmacology*; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D012756:Sheep; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
D006835:Hydrazones; D007659:Ketones; D063065:Organophosphonates; D015800:Protozoan Proteins; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D010732:Phosphofructokinase-1; C022502:pyrophosphate-fructose 6-phosphate 1-phosphotransferase