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

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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.

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Acknowledgment

This work was financially supported by a grant from the Deutsche Forschungsgemeinschaft to A.H. and J.H.

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Author notes

  1. Annette Kaiser

    Present address: Fachhochschule-Bonn-Rhein-Sieg, Von-Liebig-Strasse 20, 53359, Rheinbach, Germany

Authors and Affiliations

  1. Institute for Medical Microbiolgy, Immunology and Parasitology, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany

    Sabine Specht, Salem Ramadan Sarite, Achim Hoerauf & Annette Kaiser

  2. Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistrasse 52, 20251, Hamburg, Germany

    Ilona Hauber & Joachim Hauber

  3. Institute of Organic Chemistry, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany

    Ulf F. Görbig & Chris Meier

  4. MondoBiotech AG, Hardstrasse 53, 4052, Basel, Switzerland

    Dorian Bevec

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  1. Sabine Specht
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  2. Salem Ramadan Sarite
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Correspondence to Annette Kaiser.

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Specht, S., Sarite, S.R., Hauber, I. et al. The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria—inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase. Parasitol Res 102, 1177–1184 (2008). https://doi.org/10.1007/s00436-008-0891-x

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  • DOI: https://doi.org/10.1007/s00436-008-0891-x

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