The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase.
Malaria is still a major cause of death in the tropics. There is an urgent need for new anti-malarial drugs because drug-resistant plasmodia frequently occur. Over recent years, we elucidated the biosynthesis of hypusine, a novel amino acid contained in eukaryotic initiation factor 5A (eIF-5A) in Plasmodium. Hypusine biosynthesis involves catalysis of deoxyhypusine synthase (DHS) in the first step of post-translational modification. In a screen for new inhibitors of purified plasmodium DHS, CNI-1493, a novel selective pro-inflammatory cytokine inhibitor used in clinical phase II for the treatment of Crohn's disease, inhibited the enzyme of the parasite 3-fold at a concentration of 2 microM. In vitro experiments with 200 microM CNI-1493 in Plasmodium-infected erythrocytes, which lack nuclei and DHS protein, showed a parasite clearance within 2 days. This can presumably be attributed to an anti-proliferating effect because of the inhibition of DHS by the parasite. The determined IC50 of CNI-1493 was 135.79 microM after 72 h. In vivo application of this substance in Plasmodium berghei ANKA-infected C57BL/6 mice significantly reduced parasitemia after dosage of 1 mg/kg or 4 mg/kg/body weight and prevented death of mice with cerebral malaria. This effect was paralleled by a decrease in serum TNF levels of the mice. We suggest that the new mechanism of CNI-1493 is caused by a decrease in modified eIF-5A biosynthesis with a downstream effect on the TNF synthesis of the host. From the current data, we consider CNI-1493 to be a promising drug for anti-malarial therapy because of its combined action, i.e., the decrease in eIF-5A biosynthesis of the parasite and host cell TNF biosynthesis.
Specht
Sabine
S
Institute for Medical Microbiolgy, Immunology and Parasitology, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Sarite
Salem Ramadan
SR
Hauber
Ilona
I
Hauber
Joachim
J
Görbig
Ulf F
UF
Meier
Chris
C
Bevec
Dorian
D
Hoerauf
Achim
A
Kaiser
Annette
A
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D018512:Parasitemia / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000813:Anilides; D006146:Guanidines
D000962:Antimalarials; D004791:Enzyme Inhibitors; D006835:Hydrazones; D000587:Oxidoreductases Acting on CH-NH Group Donors; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines; C063507:deoxyhypusine synthase