Previously unknown protective enzyme identified in the sleeping sickness parasite.


African sleeping sickness is caused by the single-cell parasite Trypanosoma brucei and is spread by infected tsetse flies in sub-Saharan Africa. The disease is deadly, affecting both humans and livestock and can erupt into epidemics of between 20,000 and 500,000 people. In the last decade, the number of cases has been limited by discovering patients and treating them before they carry the disease on.  However, the global medical community have warned that an increased resistance against antibiotics among parasites can lead to an intensification in the number of cases once more.

At present, no vaccine exists and the only pharmaceuticals available are highly toxic or can only be used on some variants or stages of the disease. The only medication that can treat all forms of the disease in humans is Melarsoprol, which in 5-10% of cases leads to fatal brain damage.  Now, a study from researchers led by Umeå University shows that the parasite causing sleeping sickness has a defence mechanism against potential pharmaceuticals under development against the disease. The team state that the deadly parasite has a previously unknown enzyme that can cleave and disarm adenosine analogue pharmaceuticals. The opensource study is published in the Journal of Biological Chemistry.

Previous studies show that to survive the Trypanosoma parasite is fully dependent on purines, nutrients absorbed from the blood and used as building blocks to produce RNA and DNA. This dependency is something currently being exploited in the development of pharmaceuticals.  Recent studies in animal models show promising results with adenosine analogues, a drug group usually used on other diseases.  The idea is to develop adenosine analogues that are similar to natural purines and are therefore absorbed by the parasites to subsequently kill them. These substances can be used to cure mice infected with the disease but have so far not been tested on human sleeping sickness patients.  Also, researchers have been unaware as to why some adenosine analogues work against sleeping sickness whereas others don’t.  The current study shows that the parasite has an enzyme able to cleave adenosine analogues at low concentrations which provides an explanation of why some drugs work and others don’t.

The current study used radioactive tracer to show that the parasites are partially protected against lower concentrations of adenosine by the ability to cleave it and use the adenine for ATP synthesis.  Results show that T. brucei methylthioadenosine phosphorylase (TbMTAP) was found to be responsible for the cleavage as indicated by cell extracts and TbMTAP-knockdown cells.

The lab state that a major reason why the protection system fails in high concentrations of adenosine, is that

adenine phosphoribosyltransferase (APRT) does not metabolize the adenine efficiently enough. The role of APRT in this pathway was supported by the observation that knockout cells lacking this enzyme showed enhanced sensitivity to adenosine.

The team surmise that their findings enable the global medical community to control adenosine analogues, that previously had low efficiency against the Trypanosoma parasite, by changing their molecular construction in order for them not to be recognised by the enzyme.  For the future, the researchers state that by rendering the inefficient drugs uncleavable, it would be possible to develop many more pharmaceutical candidates to find an efficacious drug for use on humans.

Source: Umeå University

 

Trypanosoma brucei parasites, which cause the sleeping sickness disease.  Credit: Corbis

Trypanosoma brucei parasites, which cause the sleeping sickness disease. Credit: Corbis

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