Ubiquitin–Proteasome System as a Potential Drug Target for Malaria

The ubiquitin–proteasome system is an essential protein degradation machinery responsible for maintaining cellular protein homeostasis. It is a multi-subunit complex comprising of the 20S core particle and the 19S regulatory particle. Recent studies have highlighted the conservation of several subunits of the proteasome in Plasmodium, and the Plasmodium proteasome is presented as an attractive target for novel antimalarials. Several classes of proteasome inhibitors were developed from chemical libraries and were shown to have selectively potent activities against the parasite. Proteasome inhibitors have the potential to inhibit all the stages of the parasite as well as different strains, including the drug-resistant parasites. Proteasome inhibitors have also been shown to act synergistically with artemisinin, which might be useful in combating drug resistance. This chapter highlights the different classes of proteasome inhibitors developed including β-lactones, peptide aldehydes, α′β′ epoxyketone, asparagine ethylene diamines, peptide sulphonyl fluorides, peptide boronates, and cyclic peptides. This chapter also highlights how the proteasome inhibitors are validated through in vitro evolution techniques. Rapid progress in the field together with available cryo-EM structure of the Plasmodium 20S proteasome, shows great promise for developing proteasome inhibitors as novel antimalarials.