In what is billed as a major breakthrough for the treatment of sleeping sickness and neglected diseases in general, scientists at the University of Dundee in Scotland have identified a valid drug target and progressed to lead optimisation with potential low-toxicity, orally administered compounds for the fatal parasitic disease human African trypanosomiasis (HAT).

Drugs could be ready for clinical trials in around 18 months, say researchers at Dundee University’s Drug Discovery Unit (DDU), who worked on the project with partners at the University of York in the UK and the Structural Genomics Consortium in Toronto, Canada. The new approach to tackling HAT is described in the latest edition of the journal Nature.

With increasing reports of treatment failures with the two currently available drugs for HAT, one of which has fatal side effects in around 5% of patients, there is a particularly urgent need for new options, the DDU notes. The World Health Organization (WHO) estimates that around 50,000 to 70,000 people in sub-Saharan Africa are infected with the disease each year.

The drug development process has also been complicated by a shift in WHO priorities towards the second stage of the disease, due to concerns over dwindling efficacy of the current stage-two drugs. The DDU’s initial aim was to develop a safe, convenient treatment for the first stage of the disease.

According to Professor Paul Wyatt, director of the Drug Discovery for Tropical Diseases programme at the University of Dundee, “we know the drug leads we have identified in [the Nature] 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 DDU’s compounds disrupt the enzyme N-myristoyl transferase (NMT), which is essential for the survival and growth of the parasites responsible for HAT. NMT was originally identified as a drug target for HAT by Professor Debbie Smith’s group at the York Centre for Immunology and Infection. Working with colleagues from the York Structural Biology Lab, Professor Smith’s team also developed the assay and materials for screening in Dundee.

Dr Ray Hui’s group at the Structural Genomics Consortium in Toronto produced a three-dimensional representation of how the new molecules interact with NMT, which contributed significantly to the design of better compounds.

The second stage of HAT is particularly difficult to treat in poverty-stricken rural areas, where many of the people who contract the disease live, the DDU points out. Of the two drugs available for HAT, the arsenic derivative melarsoprol has fatal side-effects in around one in 20 patients, while eflornithine is costly, requires prolonged hospital treatment and is not effective against all forms of the disease, the Dundee researchers say.

Pharma partner sought

Professor Wyatt described the DDU’s breakthrough on new approaches to HAT as “one of the most significant findings made in recent years in terms of drug discovery and development of neglected diseases”. The next step will be preclinical testing, after which the Unit is hoping a pharmaceutical company will step in to take the programme forward.

The DDU was set up in 2005 specifically to fill a void in research and development of drug targets for diseases of poverty such as HAT, leishmaniasis and Chagas’ disease.

“There is little economic incentive for big pharmaceutical companies to engage in diseases from sub-Saharan Africa,” commented Professor Alan Fairlamb, co-founder of the DDU. “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.”

All the same, he welcomed the “positive change in attitude of major pharmaceutical companies towards some of the big neglected diseases in recent years”, adding: “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”.