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New malaria treatment thwarts parasite resistance

Research collaboration reveals promise of compounds in fight against disease

Griffith University

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IMAGE: This is professor Vicky Avery, from Griffith University's Eskitis Institute for Drug Discovery. view more

Credit: Griffith University

Scientists have made an important breakthrough in the fight against malaria, identifying a potent agent that thwarts drug resistance in the parasite that causes the disease.

In a paper published in the journal Science Translational Medicine, an international research team is reporting the effectiveness of DSM265, a long-acting inhibitor for the treatment and prevention of malaria and which kills Plasmodium falciparum in the blood and liver.

Professor Vicky Avery and Ms Sandra Duffy, from the Eskitis Institute for Drug Discovery at Griffith University (Queensland, Australia), are part of a scientific collaboration that has declared DSM265 a potential drug combination partner for either single-dose malaria treatment or once weekly doses for ongoing disease prevention.

Malaria kills around 600,000 people each year, mostly children from sub-Saharan Africa, and while treatment and insect control programs have been implemented over many years, increasing resistance in Plasmodium falciparum and Plasmodium vivax parasites in particular means current drugs are not fully effective.

According to the paper, continued progress in combating malaria requires development of new and easy to administer drug combinations with broad-ranging activity against all manifestations of the disease.

By attacking Plasmodium's ability to synthesise the nucleotide precursors required for the synthesis of DNA and RNA, the scientists say DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

DSM265 is a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH). It is the first DHODH inhibitor to reach clinical development for treatment of malaria.

"This is a very exciting time for malaria drug discovery," says Professor Avery. "The attrition rates for compounds progressing through this pipeline is considerably high, so reaching this stage is a significant milestone.

"Having compounds which are working through new mechanisms is critical for overcoming the ever growing concerns with drug resistance."

The DSM265 findings follow the announcement in June of another discovery, namely a novel antimalarial compound known as DDD107498.

Identified through collaboration between the University of Dundee's Drug Discovery Unit and Medicines for Malaria Venture - and again featuring Professor Avery's Eskitis research team -- DDD107498 has the potential to treat malaria patients in a single dose, prevent the spread of the disease from infected people, and protect a person from developing the disease in the first place.

Details of the discovery, its properties and mechanism of action have been published in the journal Nature.

"Having two new candidate compounds progressing, both with novel drug targets, is quite amazing," says Professor Avery.

"It illustrates what can be achieved when complementary teams work together. This wouldn't have been possible without the strong collaborative nature of those involved and the great leadership driving these projects forward.

"The next steps will focus on human safety and efficacy studies to ascertain whether the predictions which have been made about these compounds are founded."

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Papers available at: http://stm.sciencemag.org/content/7/296/296ra111

http://www.nature.com/nature/journal/v522/n7556/full/nature14451.html

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