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Sleeping sickness: could a new drug be in prospect?

16 Apr 2010

Paul Chinnock

Source: Nature (see original article or PDF)

Citation: Frearson JA, Brand S, McElroy SP, Cleghorn LA, Smid O, Stojanovski L, Price HP, Guther ML, Torrie LS, Robinson DA, Hallyburton I, Mpamhanga CP, Brannigan JA, Wilkinson AJ, Hodgkinson M, Hui R, Qiu W, Raimi OG, van Aalten DM, Brenk R, Gilbert IH, Read KD, Fairlamb AH, Ferguson MA, Smith DF, Wyatt PG (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature; 464(7289):728-732.


The parasitic trypanosome that causes sleeping sickness in its normal state (top) and following exposure to a treatment drug. [Credit: University of Dundee.]

Major advances in drug discovery for the infectious diseases of poverty are rare; the level of research taking place on these neglected conditions is still inadequate. Much to be welcomed, therefore, are new findings [1] reported in Nature by researchers working on sleeping sickness (human African trypanosomiasis [HAT]), a disease that is responsible for around 30,000 deaths in Africa every year. Their work has led to the identification of a new molecular target for drugs against this disease and a series of associated “lead compounds” that can now be further researched to determine their potential as HAT treatments.

In collaboration with partners at the University of York and the Structural Genomics Consortium in Canada, scientists in the Drug Discovery Unit (DDU) at the University of Dundee in Scotland followed a lead from earlier studies that found that Trypanosomiasis brucei, the parasite that causes HAT, cannot grow without a naturally occurring protein called N-myristoyltransferase (NMT). An enzyme that affixes chains of fatty acids to other proteins, NMT acts on at least 60 other proteins in the cell. And interfering with it, the researchers discovered, has dramatic effects on the parasite, rapidly killing it both in vitro and in vivo.

The ideal treatment for the disease would be oral, of low toxicity, simple to use, easy to store, effective in both early and advanced stages, and active against the different forms of HAT found in different parts of Africa. Crucially, it must also be affordable. None of the four drugs currently in use meets these criteria. The most widely used drugs are melarsoprol (which is arsenic-based and kills up to one in twenty patients who receive it) and eflornithine, which requires a slow infusion every six hours for fourteen days making it expensive and unsuitable for use in the very countries where the disease is most common. [A trial, highlighted in TropIKA.net last year found that eflornithine infusions could be reduced to seven days if combined with oral nifurtimox, a drug already used in the treatment of Chagas disease.]

According to Professor Paul Wyatt, director of the Drug Discovery for Tropical Diseases Program at Dundee, the new finding could lead to the development of drugs that do fulfil the above criteria, calling it “one of the most significant made in recent years in terms of drug discovery and development for neglected diseases”.

“We now have a valid drug target for HAT and have found leads for drugs which can be dosed orally,” says Professor Wyatt. “These two findings represent significant strides in the development of a full-blown drug against sleeping sickness suitable for clinical trials. HAT comes in two stages ­– we know the drug leads we have identified in this paper can treat the first stage and we are very optimistic that we can now further develop them to treat the second, more serious stage”. The researchers believe that the drugs can be ready for human clinical trials in around 18 months.

If the trials are successful, the drug will then have to be manufactured on a large scale, and a major barrier will then be the reluctance of big pharmaceutical companies to devote resources to producing a drug for a disease that is confined to sub-Saharan Africa. Professor Fairlamb, also of Dundee, said, “We’ve seen that these companies are now looking to Asia and Latin America as emerging markets, but one doesn’t exist in Africa yet”. Nevertheless, he continued, “We welcome the positive change in attitude of major pharmaceutical companies towards some of the big neglected diseases in recent years. We hope to go into partnership with a pharmaceutical company once we have a candidate drug that has passed all the necessary preclinical safety and efficacy tests”.

See also press release from the University of Dundee. [The Nature article itself is not available with open access. To read it, a subscription to the journal is therefore required. In some developing countries, access may be possible via the HINARI programme.]

The new findings have been published within a few days of a historical review [1] of the development of the four existing drugs for HAT: suramin, pentamidine, melarsoprol and eflornithine. (Eflornithine, originally developed in the 1970s as an anti-cancer drug, became a treatment for sleeping sickness largely by accident.)

References

  1. Steverding D (2010). The development of drugs for treatment of sleeping sickness: a historical review. Parasit Vectors; 3(1):15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20219092

2010 Nature Publishing Group

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