Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Abstract

The eukaryotic pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania are responsible for debilitating diseases that affect millions of people worldwide. The numbers of drugs available to treat these diseases, Human African Trypanosomiasis, Chagas' disease and Leishmaniasis are very limited and existing treatments have substantial shortcomings in delivery method, efficacy and safety. The identification and validation of novel drug targets opens up new opportunities for the discovery of therapeutic drugs with better efficacy and safety profiles. Here, the potential of targeting the ubiquitin-proteasome system in these parasites is reviewed. Ubiquitination is the posttranslational attachment of one or more ubiquitin proteins to substrates, an essential eukaryotic mechanism that regulates a wide variety of cellular processes in many different ways. The best studied of these is the delivery of ubiquitinated substrates for degradation to the proteasome, the major cellular protease. However, ubiquitination can also regulate substrates in proteasome-independent ways, and proteasomes can degrade proteins to some extent in ubiquitin-independent ways. Because of these widespread roles, both ubiquitination and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well.

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

“…Although it has not yet been extensively investigated in kinetoplastids, data from genome-wide RNAi and the use of pharmacological inhibitors of trypanosome 26S proteasome have demonstrated the presence of an ERQC system in trypanosomes. Consistently, genes encoding for orthologues of ubiquitin E1, E2 and E3 proteins are also present in these parasites (Field et al, 2010;Gupta et al, 2018;Bijlmakers, 2021). In higher eukaryotes, UBA1 is the E1 ubiquitin protein responsible for more than 90% of all ubiquitination processes.…”

Exploring direct and indirect targets of current antileishmanial drugs using a novel thermal proteomics profiling approach

“…Selection of stress response-associated proteins through TPP-TR upon AmB or MF treatment could point to “innate” strategies used by L. infantum to survive in stressful environments. It is also worthy to note that in AmB and MF TPP-TR experiments we were able to detect a significant T m shift for various components of the proteasome, whose inhibition is known to trigger proteotoxic stress in the parasite ( Bijlmakers, 2020 ). Curiously, the TPP-TR approach also highlighted proteins previously reported to elicit protective immunity against VL, such as EF-1alpha and HSP83 ( Kaur et al., 2011 ; Sabur et al., 2018 ).…”

Plant Terpenoids as Hit Compounds against Trypanosomiasis

“…NMT is also present in humans, but T. brucei is extremely sensitive to NMT inhibition, probably because endocytosis occurs at a very high rate in T. brucei [ 36 ]. Recently, significant progress in targeting the ubiquitin-proteasome system was reported [ 37 ]. The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes and is essential for the survival of eukaryotes including trypanosomatids.…”