Sleeping sickness—a new cure for a neglected disease?

Scientists have validated a new drug target, the Trypanosoma brucei enzyme N-myristoyltransferase, in the fight against sleeping sickness, and have already identified and tested an inhibitor against this enzyme that successfully cures T. brucei infection in mice.

The study, published in the journal Nature, provides a much-needed boost to research into neglected tropical diseases, which are often associated with poverty.

Image provided by Wikipedia

Sleeping sickness—also known as African trypanosomiasis—is a disease caused by by the parasite T. brucei, which itself is transmitted to humans via the tsetse fly. African trypanosomiasis is endemic in regions of Sub-Saharan Africa and WHO estimates suggest that 50,000-70,000 people are currently infected with the parasite and 30,000 people die from the infection every year. The disease can cause significant morbidity and mortality and consists of two stages; stage 1, where parasites are present in the blood, lymph and interstitial fluid, and the more serious stage 2, with parasites present in the central nervous system (CNS). Without treatment, the severe neurological symptoms of the disease—confusion, extreme fatigue and sleep cycle disturbances—can ultimately lead to an irreversible and progressive mental decline ending in coma and death.

The few treatments available in our arsenal against African trypanosomiasis are out-dated and can have poor efficacy and serious side effects. Previous work has already proposed that N-myristoyltransferase is a potential target for the treatment of parasitics diseases, including African trypanosomiasis. This enzyme adds myristate (a common saturated fatty acid) to many eukaryotic and microbial proteins, a process which is required for their biological activity. Julie Frearson and colleagues, have now made a breakthrough in the discovery and development of effective, low toxicity drugs to treat sleeping sickness by investigating compounds that affect T. brucei N-myristoyltransferase.

The researchers first screened a library of 62,000 lead-based compounds to test their effectiveness at inhibiting N-myristoyltrasnferease and in preventing proliferation of the blood stage form of T. brucei. They found one compound—DDD85646—was very potent at inhibiting myristoylation and trypanosome growth during in vitro tests. The scientists then tested the efficacy of this compound in animal models of trypanosomiasis. They found that DDD85646 was well-tolerated and effectively cured acute trypanosomiasis in mice. Furthermore, DDD85646 is trypanocidal—it rapidly killed trypanosomes in both in vitro and in vivo assays. Finally, the investigators confirmed that DDD85646 truly acts “on target” against the T. brucei N-myristoyltransferase, and they also characterised the peptide pocket in which the inhibitor binds the target enzyme.

A possible drawback in using an inhibitor against N-myristoyltransferase as a trypanocidal drug is that humans also produce this enzyme. More research is needed into the inhibitor DDD85646 to improve its selectivity (ensuring that it is specific only for ­N-myristoyltransferase produced by trypanosomes) and to determine whether it can also penetrate the CNS and effectively kill parasites during the late-stage of trypanosomiasis. Crucially, clinical trials will be needed to ensure the compound is safe to use in humans. Only then will any future drugs for sleeping sickness, based on this research by Frearson et al., be seriously considered for production by big pharmaceutical companies.

ResearchBlogging.orgFrearson, J., Brand, S., McElroy, S., Cleghorn, L., Smid, O., Stojanovski, L., Price, H., Guther, M., Torrie, L., Robinson, D., Hallyburton, I., Mpamhanga, C., Brannigan, J., Wilkinson, A., Hodgkinson, M., Hui, R., Qiu, W., Raimi, O., van Aalten, D., Brenk, R., Gilbert, I., Read, K., Fairlamb, A., Ferguson, M., Smith, D., & Wyatt, P. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness Nature, 464 (7289), 728-732 DOI: 10.1038/nature08893

*see also African trypanosomes just love social networking

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Filed under Infectious Disease, Microbiology, Public Health

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