Last Updated: 30/06/2024
Proteasome inhibitors as new potent resistance-reversing antimalarials
Objectives
The Project aimed to establish assays that can be used to identify compounds with plasmodium-specific proteasome inhibitory activity, killing activity against Plasmodium falciparum cultures, and low mammalian cell toxicity.
Specific objective was to establish a working relationship with Takeda, Japan’s largest pharmaceutical company, with a view to screening relevant Takeda libraries to identify a suitable proteasome inhibitor combination that can be translated to clinical use to overcome artemisinin resistance.
In work leading to this project, we found that inhibitors of the plasmodium proteasome a proteinase complex that plays a critical role in degrading unfolded proteins – show parasiticidal activity against both artemisinin sensitive and resistant parasite – at all stages of intraerythroctyic development. This includes the young (ring stage) form of the parasite, which is resistant to most other chemotherapeutic agents.
Moreover the researchers found that inhibitors of the proteasome strongly synergize artemisinin-mediated killing of P. falciparum in cultures of both sensitive and resistant strains. Importantly, efficacy of the combination was also observed against P. berghei in a mouse model of malaria in vivo. This indicates that a suitable proteasome inhibitor (i.e. with P. falciparum-specific activity) would be a promising lead in its own right and, would be particularly effective in combinations with artemisinins.
Jan 2015
$297,134
