PROTEASOME INHIBITORS BLOCK DEVELOPMENT OF PLASMODIUM SPP

Proteasomes degrade most of the proteins inside eukaryotic cells, incl uding transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of t he exoerythrocytic and erythrocytic stages of the malaria parasite, Al though lactacystin-treated Plasmodium berghei sporozoites are still in vasive, their development into exoerythrocytic forms (EEF) is inhibite d in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vi tro is also profoundly inhibited when drug treatment of the synchroniz ed parasites is prior, but not subsequent, to the initiation of DNA sy nthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, bu t the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp,, these findings highlight the potential of proteas ome inhibitors as drugs for the treatment of diseases caused by protoz oan parasites.