Ubiquitin Proteasome System as a Potential Drug Target for Malaria

Abstract

Parasites of Plasmodium genus are responsible for causing malaria in humans. Resistant strains to all available antimalarials can be found in several locations around the globe, including parasites resistant to the latest generation of combination drugs, such as piperaquine + artemisinin. Plasmodium develops between two completely different hosts such as a vertebrate one and the mosquito vector, thus it has the ability to adapt to very extreme and different environments. Through the complex life cycle in the hosts, Plasmodium invades and replicates in totally different cells thus making the study of the biology of the parasite and the identification of targets for drug development affecting all stages very difficult. It was shown that host molecules, such as melatonin and derivatives, have a role in the progression and regulation of the parasite cell cycle; In fact, when the parasite is exposed to melatonin there is an increase in transcription levels of genes encoding for proteins related to the Ubiquitin Proteasome (UPS) System. This system is essential for the survival of the parasite, and drugs such as bortezomib, MLN-273, ZL3B, epoxomicins and salinosporamides are capable of eliminating the parasite by inhibiting the degradation of proteins via the proteasome system. In addition, the Plasmodium UPS shows low similarity to the ubiquitin proteasome system in Humans; the identification of unique targets to be used for therapeutic molecules development increases the importance of UPS studies in malaria challenging. Drugs that cause oxidative stress, such as artemisinin, show a strong synergistic effect with proteasome inhibitors, increasing the possibilities of combined therapies, which are more effective with lower concentration of drugs. Thus, the study of the mechanism of action of the UPS and the identification of potential targets for new drugs development are promising alternative strategies to fight the drug-resistance problem in malaria parasites.

The interaction of hepatitis B virus with the ubiquitin proteasome system in viral replication and associated pathogenesis

“…Although the precise mechanisms associated with the role of HBx in viral infection remain to be understood, the reviewed studies support that modulation of the host UPS by HBx plays an important role in regulating HBV replication and the pathogenesis of liver diseases, especially HCC. Significant progress has been made in identifying the molecules that target specific UPS components as a potential target for different disease therapies [99–101]. A further understanding of the complicated interactions between the HBV and the host UPS, particularly the HBx-UPS interaction, could provide novel insight into the mechanisms of viral pathogenesis, and help determine potential therapeutic strategies involving targeting the UPS to block HBV infection and associated liver diseases.…”

Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome

“…The reversible, covalent peptide boronate proteasome inhibitors bortezomib and ixazomib are used clinically to treat multiple myeloma. Ixazomib is administered orally and offers a favorable efficacy/safety profile with weekly dosing delivered as a fixed dose. , Bortezomib has been shown to have activity against P. falciparum , ,, although it has not been formally demonstrated that this results from inhibition of the P. falciparum proteasome. In this work, we used in vitro directed evolution to generate bortezomib-resistant parasites, thereby validating the β5 subunit of the proteasome as the target.…”

UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

“…This process is a component of the ubiquitin-proteasome system (UPS) that regulates protein turnover in cells [14]. There are hundreds of enzymes involved in the addition (Ub ligases) or removal (Ub hydrolases) of ubiquitin, and the UPS has emerged as an important source of drug targets in many diseases [15][16][17][18][19][20]. Deubiquitinases (DUBs) are Ub hydrolases responsible for the removal of Ub PTMs by cleaving the isopeptide bond between the C-terminal glycine of Ub and surface lysine residues on target proteins [14].…”