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

Lindenthal, C; Weich, N; Chia, Y S; Heussler, Volker; Klinkert, M Q (2005). The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites. Parasitology, 131(Pt 1), pp. 37-44. Cambridge University Press 10.1017/S003118200500747X

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology > Malaria
08 Faculty of Science > Department of Biology > Institute of Cell Biology

UniBE Contributor:

Heussler, Volker

Subjects:

500 Science > 570 Life sciences; biology

ISSN:

0031-1820

Publisher:

Cambridge University Press

Language:

English

Submitter:

Volker Heussler

Date Deposited:

06 Jul 2016 11:26

Last Modified:

07 Jul 2016 04:35

Publisher DOI:

10.1017/S003118200500747X

PubMed ID:

16038394

BORIS DOI:

10.7892/boris.84073

URI:

https://boris.unibe.ch/id/eprint/84073

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