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New malaria treatment thwarts parasite resistance

Research collaboration reveals promise of compounds in fight against disease

Date:
July 17, 2015
Source:
Griffith University
Summary:
As increasing resistance in parasites undermines the effectiveness of current drugs, two new compounds are raising hopes in the ongoing battle against malaria, scientists report.
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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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Journal References:

  1. M. A. Phillips, J. Lotharius, K. Marsh, J. White, A. Dayan, K. L. White, J. W. Njoroge, F. El Mazouni, Y. Lao, S. Kokkonda, D. R. Tomchick, X. Deng, T. Laird, S. N. Bhatia, S. March, C. L. Ng, D. A. Fidock, S. Wittlin, M. Lafuente-Monasterio, F. J. G. Benito, L. M. S. Alonso, M. S. Martinez, M. B. Jimenez-Diaz, S. F. Bazaga, I. Angulo-Barturen, J. N. Haselden, J. Louttit, Y. Cui, A. Sridhar, A.-M. Zeeman, C. Kocken, R. Sauerwein, K. Dechering, V. M. Avery, S. Duffy, M. Delves, R. Sinden, A. Ruecker, K. S. Wickham, R. Rochford, J. Gahagen, L. Iyer, E. Riccio, J. Mirsalis, I. Bathhurst, T. Rueckle, X. Ding, B. Campo, D. Leroy, M. J. Rogers, P. K. Rathod, J. N. Burrows, S. A. Charman. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Science Translational Medicine, 2015; 7 (296): 296ra111 DOI: 10.1126/scitranslmed.aaa6645
  2. Beatriz Baragaña, Irene Hallyburton, Marcus C. S. Lee, Neil R. Norcross, Raffaella Grimaldi, Thomas D. Otto, William R. Proto, Andrew M. Blagborough, Stephan Meister, Grennady Wirjanata, Andrea Ruecker, Leanna M. Upton, Tara S. Abraham, Mariana J. Almeida, Anupam Pradhan, Achim Porzelle, María Santos Martínez, Judith M. Bolscher, Andrew Woodland, Suzanne Norval, Fabio Zuccotto, John Thomas, Frederick Simeons, Laste Stojanovski, Maria Osuna-Cabello, Paddy M. Brock, Tom S. Churcher, Katarzyna A. Sala, Sara E. Zakutansky, María Belén Jiménez-Díaz, Laura Maria Sanz, Jennifer Riley, Rajshekhar Basak, Michael Campbell, Vicky M. Avery, Robert W. Sauerwein, Koen J. Dechering, Rintis Noviyanti, Brice Campo, Julie A. Frearson, Iñigo Angulo-Barturen, Santiago Ferrer-Bazaga, Francisco Javier Gamo, Paul G. Wyatt, Didier Leroy, Peter Siegl, Michael J. Delves, Dennis E. Kyle, Sergio Wittlin, Jutta Marfurt, Ric N. Price, Robert E. Sinden, Elizabeth A. Winzeler, Susan A. Charman, Lidiya Bebrevska, David W. Gray, Simon Campbell, Alan H. Fairlamb, Paul A. Willis, Julian C. Rayner, David A. Fidock, Kevin D. Read, Ian H. Gilbert. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, 2015; 522 (7556): 315 DOI: 10.1038/nature14451

Cite This Page:

Griffith University. "New malaria treatment thwarts parasite resistance: Research collaboration reveals promise of compounds in fight against disease." ScienceDaily. ScienceDaily, 17 July 2015. <www.sciencedaily.com/releases/2015/07/150717101407.htm>.
Griffith University. (2015, July 17). New malaria treatment thwarts parasite resistance: Research collaboration reveals promise of compounds in fight against disease. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2015/07/150717101407.htm
Griffith University. "New malaria treatment thwarts parasite resistance: Research collaboration reveals promise of compounds in fight against disease." ScienceDaily. www.sciencedaily.com/releases/2015/07/150717101407.htm (accessed May 23, 2017).

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