Abstract
Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.
Highlights
Human African Trypanosomiasis (HAT), often referred to as sleeping sickness, is a neglected tropical disease prevalent in the African continent in an area delineated by the Sahara, Kalahari, and Namibian deserts [1]
Each group was infected with a different strain: New York “single marker” cells (NY-SM) +, NY-SM—(not induced with tetracycline), adenosine kinase (ADKIN) A + (NY-SM cells transfected with RNA interference (RNAi) insert Tb927.6.2300 and pre-induced with tetracycline in vitro), and ADKIN A—(NY-SM cells transfected with
The role of 4Einteracting protein (4EIP) RNAi-mediated knockdown (NY-SM cells transfected with RNAi insert Tb927.9.11050) and knockout (4EIP-KO and 4EIP-AB strains) in in vivo infectivity was evaluated in a similar manner as described above
Summary
Human African Trypanosomiasis (HAT), often referred to as sleeping sickness, is a neglected tropical disease prevalent in the African continent in an area delineated by the Sahara, Kalahari, and Namibian deserts [1]. Given that the parasite lacks de novo purine synthesis and solely depends on purine salvage [11], interaction with the involved pathways represents a valid strategy to explore novel antitrypanosomal drugs Nucleoside analogues such as tubercidin and cordycepin were already proven active against T. brucei [12,13,14,15]. Genome-wide RNA interference (RNAi) screening is a powerful tool for the unbiased identification of genes involved in the MoA of novel compounds [24] This technique has been applied to the current antitrypanosomal drugs confirming the involvement of known drug targets, such as the amino acid transporter 6 (AAT6) for eflornithine and nitroreductase (NTR) for benznidazole and nifurtimox [25,26,27,28]. MoA of tubercidin analogues that may represent potential novel drug targets given their essentiality for T. brucei infectivity
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