Dundee Drug Discovery Unit makes breakthrough in sleeping sickness therapy
Researchers at the University of Dundee identify new treatments for sleeping sickness.
Scientists from the Drug Discovery Unit (DDU) at the University of Dundee, working together with partners at the University of York and the Structural Genomics Consortium in Toronto, have made a major breakthrough in identifying new treatments for the disease known as sleeping sickness.
In a paper published in the Journal Nature*, the researchers describe a new approach to tackling the fatal parasitic disease human African trypanosomiasis (HAT), commonly known as sleeping sickness due to disturbance of the sleep cycle caused by parasites infecting the brain.
'This is one of the most significant findings made in recent years in terms of drug discovery and development for neglected diseases,' said Professor Paul Wyatt, Director of the Drug Discovery for Tropical Diseases programme at Dundee.
'We now have a valid drug target for HAT and have found leads for drugs which can be dosed orally. 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.'
It is estimated that drugs may be ready for human clinical trials in around 18 months.
The World Health Organisation estimates around 50,000-70,000 people in sub-Saharan Africa are infected with the disease, which is spread by the bite of a tsetse fly.
The disease has two stages, the second of which is particularly difficult to treat in poverty-stricken rural areas, where many victims live. Of the two drugs currently available, one - an arsenic-based drug - has fatal side effects in around one in 20 patients, and the other, eflornithine, is costly, requires prolonged hospital treatment and is not effective against all forms of the disease.
In response to the need for new and safe treatments, the DDU has already made good progress in developing compounds that have proved effective at killing the parasites, and that work well in the first stage of the disease. The compounds disrupt the enzyme N-myristoyl transferase, or NMT for short, which is essential for survival and growth of the parasites.
'The process of developing drugs consists of a number of hurdles which have to be passed,' said Professor Wyatt. 'The first is identifying an Achilles heel of the parasite, such as an enzyme which is essential for the survival of the parasites, known as a drug target.
'The second is to confirm that molecules can disrupt these targets and so kill the parasite, a process called 'target validation'. The next is 'lead optimization' to develop these early molecules into candidate drugs for clinical trials. That is where we are now. The final hurdle is to show safety and efficacy of the new drug in patients.'
Dr Ray Hui's group within the SGC produced a three-dimensional representation of how the new molecules interact with NMT. This information greatly aids the design of better compounds and can accelerate the discovery of new drug candidates.
The Drug Discovery Unit at Dundee was formed in 2005 specifically to fill the void of research and development of drug targets for diseases of poverty like African sleeping sickness, leishmaniasis, and Chagas' disease that afflict the developing world.
* Nature 464, 728-732