Exploiting the Achilles’ heel of membrane trafficking in trypanosomes

Abstract

HighlightsDevelopment of new drugs against trypanosomes is a crucial but unmet need.Membrane transport, endocytosis and related processes have been proposed as drug targets.Recent insights uncovered the mode of action of two drugs that are already in the clinic.Both of these drugs, suramin and pentamidine, bind surface proteins.It is possible that endocytosis is a common component of sensitivity to suramin and pentamidine.

Drug resistance in protozoan parasites

“…phenanthridines, diamidines [24][25][26]), or e.g. to haem (chloroquine [27]), or be more generally cytotoxic, with multiple targets ( polypharmacology), as may be the case for heavy metal drugs (arsenicals, antimonials) and suramin [28], in which case selectivity depends mostly on selective entry into the parasite rather than into the host cells, through unique transporters or other uptake mechanisms [20,28,29].…”

“…As explained by Graf et al [34], the pharmacokinetics of pentamidine (but not of melarsoprol), especially the high peak plasma concentration and long clearance time, may prevent treatment failure even though the rate by which the drug enters the parasite is reduced dramatically, leading to a significant in vitro resistance phenotype. Similarly, there have been no reports of resistance to suramin, still in use for T. b. rhodesiense sleeping sickness after 100 years, and this is believed to be linked to the drug being internalised by endocytosis, which is uniquely fast in bloodstream trypanosomes, after binding to the invariant surface glycoprotein ISG75, of which there are multiple paralogues [28].…”

The Trypanosome Exocyst: A Conserved Structure Revealing a New Role in Endocytosis

“…Nutrient uptake, immune evasion, developmental progression and sensitivity to several drugs all require the action of the membrane transport system in trypanosomes [1]. In African trypanosomes, maintaining the composition and homeostasis of the surface proteome is closely connected to many of these processes, including clearance of acquired immune effectors from the surface coat, resistance to innate immune factors, uptake of heme and iron together with sensitivity to suramin and possibly additional trypanocides [2,1].…”

“…In African trypanosomes, maintaining the composition and homeostasis of the surface proteome is closely connected to many of these processes, including clearance of acquired immune effectors from the surface coat, resistance to innate immune factors, uptake of heme and iron together with sensitivity to suramin and possibly additional trypanocides [2,1]. The membrane transport system of Trypanosoma brucei is comparatively well studied, and whilst generally conserved with other eukaryotes in overall architecture [3], the system has been adapted to the parasitic life style and the specific challenges associated with survival in the mammalian bloodstream [4,5,1]. Endocytic mechanisms have received significantly more attention than secretory pathways due in part to technical tractability, but despite the clear importance of secretory pathways for the biosynthesis of the surface coat.…”

Unlocking the biological potential ofEuglena gracilis: evolution, cell biology and significance to parasitism

“…Both the cell surface and flagellum are of significant importance to life cycle progression, interactions with the environment and, in the case of parasitic trypanosomes, pathogenesis and immune evasion (Langousis andHill, 2014, Perdomo, et al, 2016). The surface macromolecules of trypanosomatids are highly lineage-specific with roles in life cycle progression (Jackson, et al, 2013, 2016, Kalb, et al, 2016, Zoltner, et al, 2016, Hovel-Miner, et al, 2016, Devault and Banuls, 2008, Chamakh-Ayari, et al, 2014, but it remains to be determined to what extent E. gracilis shares ! 4 surface protein families or other aspects of their cell biology with parasitic kinetoplastids.…”