Protein Degradation Systems as Antimalarial Therapeutic Targets

Artemisinin (ART)-based combination therapies are the most efficacious treatment of uncomplicated Plasmodium falciparum malaria. Alarmingly, P. falciparum strains have acquired resistance to ART across much of Southeast Asia. ART creates widespread protein and lipid damage inside intraerythrocytic parasites, necessitating macromolecule degradation. The proteasome is the main engine of Plasmodium protein degradation. Indeed, proteasome inhibition and ART have shown synergy in ART-resistant parasites. Moreover, ubiquitin modification is associated with altered parasite susceptibility to multiple antimalarials. Targeting the ubiquitin–proteasome system (UPS), therefore, is an attractive avenue to combat drug resistance. Here, we review recent advances leading to specific targeting of the Plasmodium proteasome. We also highlight the potential for targeting other nonproteasomal protein degradation systems as an additional strategy to disrupt protein homeostasis. Proteasome inhibitors are effective against Plasmodium spp., but past inhibitors had a low therapeutic index due to inhibition of the host enzyme complex. Recent cryo-EM data have illuminated differences between the human and P. falciparum 20S proteasome core particles, allowing the generation of P. falciparum-specific proteasome inhibitors. The recent characterization of Plasmodium proteins involved in the ubiquitin–proteasome system (UPS) has identified several enzymes, involved in attachment and removal of ubiquitin, which could be viable drug targets. Inhibitors of the human proteasome, ubiquitin E1, E2, and E3 enzymes, as well as deubiquitinating enzymes (DUBs), have been FDA-approved or are in clinical trials, demonstrating the therapeutic potential of inhibitors against these enzymes. Inhibitors to PfClp proteases are attractive since there is no human homolog to the mitochondrial-based PfClpY/Q, while PfClpC/P resides in the apicoplast, a cyanobacterial relic organelle that is not present in humans.