Identification of Small Molecules Disrupting the Ubiquitin Proteasome System in Malaria

Abstract

The ubiquitin proteasome system (UPS) is one of the main proteolytic pathways in eukaryotic cells, playing an essential role in key cellular processes such as cell cycling and signal transduction. Changes in some of the components of this pathway have been implicated in various conditions, including cancer and infectious diseases such as malaria. The success of therapies based on proteasome inhibitors has been shown in human clinical trials. In addition to its proven tractability, the essentiality of the Plasmodium falciparum UPS underlines its potential as a source of targets to identify new antimalarial treatments. Two assays, previously developed to quantify the parasite protein ubiquitylation levels in a high throughput format, have been used to identify compounds that inhibit parasite growth by targeting P. falciparum UPS. Among the positive hits, specific inhibitors of the P. falciparum proteasome have been identified and characterized. Hits identified using this approach may be used as starting points for development of new antimalarial drugs. They may also be used as tools to further understand proteasome function and to identify new targets in P. falciparum UPS.

Keywords: Plasmodium falciparum; UPS; inhibitor; proteasome; screening; ubiquitylation.