Their findings, published in the latest edition of the journal Nature, describe a new approach to tackling the disease, human African trypanosomiasis (HAT), commonly known as sleeping sickness. The new research shows promise for the development of effective, orally administered, low toxicity drugs.
Each year, around 50,000-70,000 people in sub-Saharan Africa contract the disease spread by the bite of the tsetse fly. HAT gets its more common name from the disturbance of the sleep cycle caused by the parasites infecting the brain.
We are excited that our research has contributed to development of a novel compound that kills parasites
Professor Debbie Smith
This second stage of the disease is particularly difficult to treat in poverty-stricken rural areas. 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. Increasing reports of treatment failures with these drugs is causing concern that soon there may be no effective treatment for this fatal disease.
In response to the need for new and safe treatments, a team from York’s Centre for Immunology and Infection (CII), working with the University of Dundee Drug Discovery Unit (DDU), and the University of Toronto’s Structural Genomics Consortium, has already made good progress in developing compounds that have proved effective at killing the parasites, particularly in the first stage of the disease. The compounds disrupt the enzyme N-myristoyl transferase, (NMT), which is essential for survival and growth of the parasites.
Researchers in the CII led by Professor Debbie Smith originally identified NMT as a drug target with great promise for HAT. Together with colleagues in the York Structural Biology Laboratory, Professor Smith and her team also developed the assay and materials for screening in Dundee.
Professor Smith said: “We are excited that our research has contributed to development of a novel compound that kills parasites, an important step in developing new therapeutics against this neglected tropical disease. Our early proof-of-principle studies together with recent definitive experiments confirming the specificity of the new compounds confirm the importance of working collaboratively in the quest for new drugs in this area.”
Professor Paul Wyatt, Director of the Drug Discovery for Tropical Diseases programme at Dundee, said: “This is one of the most significant findings 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. 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.”
Dr Ray Hui’s group within the SGC, at the University of Toronto, produced a three-dimensional representation of how the new molecules interact with NMT. This information aids the design of better compounds and can accelerate the discovery of new drug candidates.
Fears over the decreasing efficacy of the current stage two drugs have led the World Health Organization to shift its priorities towards a treatment for the second stage. The scientists at Dundee and York are actively working towards this new goal.
“Our initial aim was to develop a safe oral treatment for the first stage of the disease that would avoid the use of needles and be simple to use for control purposes,” explained Professor Alan Fairlamb of the DDU. “However, we are optimistic that we can address the new WHO priorities for a new treatment for the second stage of the disease.”
Professor Mike Ferguson, who established the DDU along with Professor Fairlamb, said that although there was some way to go before a new drug can be developed, the work represented a major breakthrough.
He praised Professor Smith and her colleagues at York and members of the SGC for their contributions to the project.
African sleeping sickness is neglected by large pharmaceutical companies. The shareholder value driven model of big drug companies, which works so effectively in the developed world, is not relevant to areas such as sub-Saharan Africa, where patients cannot afford their medicines.
Dr Shing Chang, R&D Director of the Drugs for Neglected Diseases Initiative, said, “This is a significant discovery. It is a good example of applying state of the art scientific knowledge and tools in a collaborative effort to address the unmet needs of neglected patients.”
Notes to editors:
- The Centre for Immunology and Infection is a joint research centre created by the University of York’s Department of Biology and the Hull York Medical School. It will shortly be expanding into a £5 million new building supported by the Higher Education Funding Council for England, the Wolfson Foundation and the Holbeck Charitable Trust.. Professor Smith’s work on NMT, supported by the Wellcome Trust, is now moving into other tropical diseases including human visceral leishmaniasis.
- The Dundee Drug Discovery Unit within the College of Life Sciences at Dundee has been created to respond to a lack of capacity in the UK for early stage drug discovery in the academic sector. The DDU’s aim is to translate basic science into lead compounds to validate putative drug targets, to use as tools to investigate disease pathways and, when appropriate, advance to pre-clinical drug candidates.
- Investors include the Wellcome Trust, the Scottish Funding Council, The Wolfson Foundation, The European Regional Development Fund, the Drugs for Neglected Diseases Initiative and the University itself.