The proteasome as a potential target for chemotherapy of African trypanosomiasis

Abstract

Trypanosomes are parasitic protozoans that afflict both man and livestock in sub-Saharan Africa. The current chemotherapy of African trypanosomiasis relies on a few drugs, most of which were developed decades ago. Combinations of toxic side effects and poor efficacy of current drugs demand an urgent need for the development of novel and effective therapeutic agents. The proteasome is a multisubunit proteinase complex that plays a critical role in intracellular protein degradation. Despite being essential to all eukaryotic cells, there are significant differences between the trypanosomal and mammalian proteasomes which makes this enzyme complex a promising target for anti-trypanosomal drug development. In this review article, the structural properties, enzymatic activities and inhibitor sensitivities of the proteasomes of Trypanosoma brucei and mammalian cells are compared. In addition, the trypanocidal activities of the different classes of proteasome inhibitors are summarized

Trypanosoma brucei: β2-selective proteasome inhibitors do not block the proteasomal trypsin-like activity but are trypanocidal

“…While there is structural and functional similarity between the trypanosomal and mammalian proteasome, there are substantial differences with respect to peptidase activity and inhibitor sensitivity. The trypanosomal proteasome has a high trypsin-like activity and a low chymotrypsin-like activity [1,2]. This is in contrast to the mammalian proteasome, which has a low trypsin-like activity and a high chymotrypsin-like activity.…”

“…The proteasome is a multi-subunit protease complex that plays a crucial role in the regulation of protein degradation in cells. Like all eukaryotic proteasomes, the 20 S core particle of the proteasome of the protozoan parasite Trypanosoma brucei has a cylindrical structure and is made up of four rings [1,2]. All essential seven α-and β-subunits have been identified as part of the trypanosomal 20 S proteasome [2,3].…”

“…Like all eukaryotic proteasomes, the 20 S core particle of the proteasome of the protozoan parasite Trypanosoma brucei has a cylindrical structure and is made up of four rings [1,2]. All essential seven α-and β-subunits have been identified as part of the trypanosomal 20 S proteasome [2,3]. Affinity-labelling experiments confirmed that also for the T. brucei 20 S proteasome the caspase-like activity, the trypsin-like activity and the chymotrypsin-like activity are associated with the β1, β2 and β5 subunits, respectively [2,4].…”

“…All essential seven α-and β-subunits have been identified as part of the trypanosomal 20 S proteasome [2,3]. Affinity-labelling experiments confirmed that also for the T. brucei 20 S proteasome the caspase-like activity, the trypsin-like activity and the chymotrypsin-like activity are associated with the β1, β2 and β5 subunits, respectively [2,4]. By using RNA interference to block selectively the expression of β-subunits, it was shown that the three catalytic subunits β1, β2, and β5 are vital for T. brucei [2,5].…”

“…The difference in activity between trypanosomal and mammalian proteasomes is corroborated by their sensitivity towards inhibitors. Inhibitor studies have shown that the trypanosomal proteasome is particularly sensitive to inhibition of the trypsin-like activity [2,[8][9][10]. The significant differences in peptidase activity and inhibitor sensitivity between the trypanosomal and mammalian proteasome make this enzyme complex a promising target for the development of urgently needed drugs for chemotherapy of African trypanosomiasis, a tropical neglected…”