The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention?

Abstract

The ubiquitin/proteasome system serves as a regulated protein degradation pathway in eukaryotes, and is involved in many cellular processes featuring high protein turnover rates, such as cell cycle control, stress response and signal transduction. In malaria parasites, protein quality control is potentially important because of the high replication rate and the rapid transformations of the parasite during life cycle progression. The proteasome is the core of the degradation pathway, and is a major proteolytic complex responsible for the degradation and recycling of non-functional ubiquitinated proteins. Annotation of the genome for Plasmodium falciparum, the causative agent of malaria tropica, revealed proteins with similarity to human 26S proteasome subunits. In addition, a bacterial ClpQ/hslV threonine peptidase-like protein was identified. In recent years several independent studies indicated an essential function of the parasite proteasome for the liver, blood and transmission stages. In this review, we compile evidence for protein recycling in Plasmodium parasites and discuss the role of the 26S proteasome as a prospective multi-stage target for antimalarial drug discovery programs.

In Vitro Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

“…It is intriguing, though, how subtle differences in structure resulted in the 10-fold difference in mean IC 50 values of BMS461996 and BMS411886. In a recent report, thiostrepton and its derivative have been shown to rapidly eliminate parasites by dually targeting the apicoplast protein synthesis and proteasome in the micromolar range (4,6,14,25). In comparison to thiostrepton, BMS461996 is water soluble and thus is biologically accessible for parasiticidal activity and results in irreversible growth inhibition within the first growth cycle, being therefore immediately effective.…”

“…These novel targets/mechanisms include but are not limited to the protein synthesis machinery, DNA replication, exflagellation, and proteasome pathways. All of these biochemical processes are critical for parasite survival, development, and transition from the asexual blood stages to gametocytes (4). The current antibiotics for the treatment of malaria infection include doxycycline, azithromycin, tetracycline, and clindamycin (5).…”

Protein Degradation Systems as Antimalarial Therapeutic Targets

“…E4 ubiquitin chain elongation factor can further polyubiquitinate polypeptides [44]. Ubiquitin and its E1, E2, E3, and E4 enzymes are expressed throughout the asexual blood stages [32, 38, 41, 45]. Molecular characterization of a set of E1, E2, and E3 enzymes revealed significant functional conservation in Plasmodium .…”

Structural characterization, ROS-inductive and proteasome inhibitory properties of ternary and binary copper(II) complexes of N2- and N2O2-ligands

“…Proteasome inhibitors have potential to treat a wide variety of diseases, including T.B. bacterial infection, cancer and against parasitic protozoa [7,[66][67][68]. The 20S proteasome has three types of proteolytic sites, viz.…”