The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase.

Abstract

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.

• Authors: Sabine Specht, Salem Ramadan Sarite, Ilona Hauber, Joachim Hauber, Ulf F Görbig, Chris Meier, Dorian Bevec, Achim Hoerauf, Annette Kaiser
• Journal: Parasitology research (Parasitol Res) Vol. 102 Issue 6 Pg. 1177-84 (May 2008) ISSN: 0932-0113 [Print] Germany
• PMID: 18256853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Enzyme Inhibitors
• Hydrazones
• Protozoan Proteins
• Tumor Necrosis Factor-alpha
• semapimod
• Oxidoreductases Acting on CH-NH Group Donors
• deoxyhypusine synthase

Topics

• Animals
• Antimalarials (pharmacology)
• Enzyme Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Hydrazones (administration & dosage, pharmacology, therapeutic use)
• Inhibitory Concentration 50
• Malaria (drug therapy)
• Mice
• Mice, Inbred C57BL
• Oxidoreductases Acting on CH-NH Group Donors (antagonists & inhibitors)
• Parasitemia (drug therapy)
• Parasitic Sensitivity Tests
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Protozoan Proteins (antagonists & inhibitors)
• Survival Analysis
• Tumor Necrosis Factor-alpha (blood)