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The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites

Published online by Cambridge University Press:  09 March 2005

C. LINDENTHAL ,
N. WEICH ,
Y.-S. CHIA ,
V. HEUSSLER  and
M.-Q. KLINKERT
C. LINDENTHAL
Affiliation:
Pharmaceutical Biotech Production, Roche Diagnostics GmbH, Penzberg, Germany
N. WEICH
Affiliation:
Millenium Pharmaceuticals Inc., Cambridge, MA 02139, USA
Y.-S. CHIA
Affiliation:
Department of Molecular Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
V. HEUSSLER
Affiliation:
Department of Molecular Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
M.-Q. KLINKERT
Affiliation:
Department of Molecular Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
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Abstract

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

Keywords

proteasome inhibitor MLN-273Plasmodiumdevelopment inhibition
Type
Research Article
Information
Parasitology , Volume 131 , Issue 1 , July 2005 , pp. 37 - 44
Copyright
© 2005 Cambridge University Press

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