Studies of the enzyme CTP synthetase in the parasite Trypanosoma brucei have brought researchers at Umeå University in Sweden closer to a cure for African sleeping sickness. Their findings are now being published in the April issue of The Journal of Biological Chemistry.
Since the parasite constantly changes its surface, it can avoid the immune defense of humans and invade the central nervous system, which leads to personality disturbances, sleep disruptions, and ultimately death. For patients affected by a severe T brucei infection in the central nervous system, there are no medicines that can treat both subspecies without incurring extremely serious side effects.
In a project directed by Professor Lars Thelander, scientists have previously discovered that the parasites’ CTP synthetase, an enzyme responsible for the production of CTP-one of the four building blocks for mRNA synthesis, a process that is critical for the survival of the parasite-should be a key target for treating the disease.
In the current publication scientists have managed to show that the proper content of acivicin, a well-known cell toxin that has previously been used as a cancer drug, can inhibit the parasite’s CTP synthetase, thereby permanently killing the trypanosomes in cell cultures. With daily doses of acivicin, trypanosome-infected mice have also been kept free of symptoms, as opposed to untreated mice that died within a few days.
“The advantage of acivicin is that it has already been used on humans. All the clinical studies have been performed, and we know that the drug can penetrate the central nervous system, which is not the case with many other medicines for trypanosomes. What’s more, it can be taken in tablet form, which is extremely important in countries with limited health-care resources,” says Artur Fijolek, co-author of the article.
The research team at the Umeå University Department of Medical Chemistry and Biophysics hopes soon to be able to find the appropriate dosage of acivicin that can permanently cure the infected mice.
Source: “Expression, Purification, Characterization and in Vivo Targeting of Trypanosome CTP Synthetase for Treatment of African Sleeping Sickness,” Artur Fijolek, Anders Hofer, and Lars Thelander. The Journal of Biological Chemistry, Vol. 282, No. 16. pp. 11858-11865, April 20, 2007..