NTD Highlight Notice: Defining and leveraging the mechanism of action of suramin for treatment of trypanosomiasis.

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Trypanosomatids are highly divergent protozoa; many, including the subject of this application, Trypanosoma brucei, are parasitic to humans and their livestock, while other species have huge impact on plants and the biosphere in general. Due to great evolutionary distance from humans, much of their biology is distinct from ours, and frequently cited as a potential opportunity for therapeutic intervention. Drug therapies are limited, with most being highly toxic and with emerging resistance. Due to complex surface architecture, vaccination is an unlikely therapeutic option. Of the available drugs, suramin, first introduced some 70 years ago, remains a drug of choice for early stage disease treatment. However, the mechanism(s) by which suramin is taken into the parasite or exerts trypanocidal activity have remained unknown. T. brucei survives for long periods within many of its mammalian hosts, facilitated by antigenic variation. A single variant surface glycoprotein (VSG) is expressed to extremely high density on the parasite surface. Periodic switching of this coat serves to prevent immunological elimination of the entire population. A second aspect of the immune evasion system is highly efficient endosomal trafficking, responsible for removing surface-bound immunoglobulin. Further, several abundant non-variant surface proteins are also known; these 'invariant' surface glycoproteins (ISGs) are also internalized extremely efficiently. Two of the ISG families, ISG65 and ISG75 are turned over comparatively rapidly, via a ubiquitin-dependent mechanism. Endocytosis then may represent an attractive means to deliver compounds to the parasite interior, if a mechanism were available to target trypanocidal agents specifically to the trypanosome. Most recently, we performed a genome wide screen using RNA interference to identify the gene products that are involved in the sensitization of trypanosomes to suramin. Many of these are involved in endocytosis, including the ISG75 family, but a substantial number have no known function. This application seeks to explore these proteins in more detail, and also to uncover additional factors that may play roles in suramin uptake and trypanocidal action. We shall examine if ISG75 represents the true receptor for suramin, link additional gene products with endocytosis, and explore the possibility of exploiting ISG75 as a means to specifically deliver trypanocidal compounds to the interior of the trypanosome, for therapeutic gain. The program of work will further improve our understanding of the mode of action of suramin, delineating pathways of interaction with the parasite in even greater detail, and offering more precisely defined therapeutic insights and targets. Further, the program will explore a potentially novel approach to delivery of trypanocidal compounds emerging from this work, which may have broad applicability.