There is welcome news for scientists working on sleeping sickness, Chagas' disease and visceral leishmaniasis: the genomes of the three trypanosome parasites responsible for these devastating illnesses have now been cracked. The sequences from Trypanosoma brucei, Trypanosoma cruzi and Leishmania major were published in last week's Science by an array of international research teams (Science 309, 416–422, 409–415, 436–442; 2005).
In the terminology of global public health, these diseases don't even fall into the category of ‘neglected diseases’ such as malaria and tuberculosis. Rather, they are classed as ‘most neglected diseases’ — which nonetheless kill millions. But those affected have little means of paying for treatment, making drug development unprofitable. Consequently, there are no vaccines, and medicines are few, expensive and usually toxic.
Treatment of sleeping sickness, for example, still relies on melarsoprol, a 50-year-old drug that is ineffective in a third of patients and kills 5% of those who take it. The high rate of fatal reactions is accepted because the disease is otherwise lethal. New therapies are clearly needed, and the availability of the parasite genomes is a step towards finding drug targets and vaccine candidates.
The three parasites share around 6,200 ‘core’ genes, so the proteins these encode might provide targets for drugs that are effective against all three. The parasites make a large and diverse set of kinase and phosphatase enzymes. This means that there could well be regulatory and other processes used by the organisms that could be vulnerable to disruption by drugs.
Many species-specific genes were also identified in the genome sequences, providing potential species- and stage-specific targets. Although the three parasites share many subcellular structures, such as kinetoplasts and glycosomes, the organisms are very different. They are spread by different insects, attack different tissues and cause different pathologies. The specimens of L. major pictured are in the form that is transmitted to humans by sand flies.
Each parasite also has its own mechanism for evading the human immune system: T. brucei does not enter its victim's cells, and evades the immune system by constantly changing its main surface proteins; T. cruzi holes up inside cells, but uses a similar strategy to hide from the immune system; and L. major infects certain immune cells and interferes with their function.
Producing effective treatments against these parasites will be a lengthy process, but initial research is already under way by not-for-profit drugs groups such as the Institute for OneWorld Health (http://www.oneworldhealth.org) and the Drugs for Neglected Diseases Initiative (http://www.dndi.org). The genome sequences will provide such initiatives with a wealth of data and leads.
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Biochemical characterization of a protein tyrosine phosphatase from Trypanosoma cruzi involved in metacyclogenesis and cell invasion
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Protein kinases as targets for antimalarial intervention: Kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes
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