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Drug Breakthrough in Fight Against Neglected Diseases

Published: Thursday, April 01, 2010
Last Updated: Thursday, April 01, 2010
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Scientists have made a major breakthrough in identifying new treatments for a fatal disease which infects tens of thousands of Africans each year.

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 a fatal disease which infects tens of thousands of Africans each year.

Their findings, published in the latest edition of the scientific journal Nature, 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.

The breakthrough made at Dundee shows promise for the development of effective, orally administered, low toxicity drugs to treat sleeping sickness.

“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.

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.”

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.”

The Dundee team worked with partners from the University of York and the Structural Genomics Consortium during the course of the research.

Professor Debbie Smith’s group in York’s Centre for Immunology and Infection (CII) originally identified NMT as a drug target with great promise for HAT.  Together with colleagues in the York Structural Biology Lab, 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”.

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.

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