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

Content Provider	Springer Nature Link
Author	Specht, Sabine Sarite, Salem Ramadan Hauber, Ilona Hauber, Joachim Görbig, Ulf F. Meier, Chris Bevec, Dorian Hoerauf, Achim Kaiser, Annette
Copyright Year	2008
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 μM. In vitro experiments with 200 μM 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 μM 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.
Starting Page	1177
Ending Page	1184
Page Count	8
File Format	PDF
ISSN	09320113
Journal	Parasitology Research
Volume Number	102
Issue Number	6
e-ISSN	14321955
Language	English
Publisher	Springer-Verlag
Publisher Date	2008-02-07
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Immunology Microbiology Medical Microbiology
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Veterinary Parasitology Insect Science

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