Targeting the Plasmodium Ubiquitin/Proteasome System with Anti- Malarial Compounds: Promises for the Future

Duk-Won      Doug Chung; Karine      G. Le Roch

Abstract

The human malarial parasite, Plasmodium falciparum, is responsible for one of the most infectious diseases of the world and is quickly gaining resistance to the commonly used antimalarial treatments. New data are continually reinforcing the idea that biological functions associated with the ubiquitin proteasome system (UPS) are not just limited to non-lysomal degradation of proteins but consist of a wide array of regulatory mechanisms such as cell cycle progression, transcriptional regulation, gene expression and trafficking. While there is much effort in understanding the UPS in many eukaryotic organisms, the Plasmodium UPS has been relatively understudied despite its potential as a therapeutic drug target. However, in vitro proteasome inhibitors studies have confirmed the essentiality of the UPS in Plasmodia with limited toxicity to human cell lines. In addition, computational studies have shown that there are a number of ubiquitinating proteins upstream of the proteasome that may serve as parasite-specific drug targets due to their variety and divergences from other eukaryotic species. In this review, we highlight the major findings about Plasmodiums UPS and discuss its possible implications as an effective and specific antimalarial target.

Keywords: Plasmodium falciparum, ubiquitin proteasome system, drug discovery, ubiquitin-ligase, malaria