Abstract
Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites’ viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6-oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have Ki values as low as 60 nM, and IC50 values in cell based assays as low as 4 μM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery.
Highlights
Trypanosoma brucei is the etiological agent of Human African Trypanosomiasis (HAT) known as “sleeping sickness”
Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei
We demonstrated that T. brucei encodes two isoforms of hypoxanthine-guanine PRTases (HGPRT) and one hypoxanthine-guanine-xanthine PRTase (HGXPRT)
Summary
Trypanosoma brucei is the etiological agent of Human African Trypanosomiasis (HAT) known as “sleeping sickness”. Once inside the mammalian host the parasite invades the bloodstream and lymph system. At this stage, the human host is mainly asymptomatic, a period that can last for months and up to years. A handful of drugs (pentamidine, eflornithine, nifurtimox, melarsoprol and suramin) is available to treat HAT at the different stages of the disease (e.g. haemo-lymphatic and brain infections). They are far from perfect drugs due to their low selectivity, high cost of production, high levels of toxicity, adverse side-effects and can have less than ideal routes of administration [4]. New and more effective drugs that can be co-administered or replace the current treatments for this disease are urgently needed
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