Potent compound inhibits protein synthesis at various stages of malaria parasite’s life-cycle
With the rapid emergence of multi-drug resistant strains of malaria, the need to find new drugs capable of delaying or preventing drug resistance has become even more urgent.
Now, an international team of researchers – including two from the University of South Florida – has discovered a promising new antimalarial drug that inhibits the production of a protein involved in the replication and transmission of the malaria parasite. If successfully developed, the new drug working in combination with an existing fast-acting antimalarial may be less likely to develop rapid resistance to major strains of malaria parasites.
Dennis Kyle, PhD, Distinguished University Health Professor, and Anupam Pradhan, PhD, a research associate, both from the USF College of Public Health Department of Global Health, were among the co-authors of the multisite preclinical study published June 18 in the journal Nature. The study was led by researchers at the University of Dundee Division of Biological Chemistry and Drug Discovery.
Dennis Kyle, PhD
The USF researchers demonstrated in a mouse model of malaria that the new drug candidate, known as DDD107498, helped block the spread of the parasitic disease with greater effectiveness than current antimalarial combination drugs. Their work was supported by a grant from Medicines for Malaria Venture.
In various preclinical studies the potent drug proved highly effective and safe while demonstrating a broad spectrum of antimalarial activity against several life-cycle stages of the malaria parasite Plasmodium falciparum. This ability to kill parasites without harmful or bothersome side effects at all stages of a complex malaria lifecycle – after the parasites enter the bloodstream through the bite of bloodstream, once they infect the liver and as soon as the modified parasites emerge from the liver to attack red blood cells – will be critical in eradicating malaria.
DDD107498 also has the potential to be administered in less costly single doses (approximately $1 per treatment) – a major advantage since the mosquito-borne disease most often affects poor people living in developing countries, particularly children and pregnant women.
Anupam Pradhan, PhD
The researchers found that DDD107498 works by blocking a molecular target identified as translation elongation factor 2 (eEF2), which is essential for protein synthesis and expressed in various life cycle stages of malaria. Its high potency and long half-life may be well suited for both preventing malaria and offering long-term protection against re-infection.
“The discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery,” the authors concluded.
Article citation:
“A novel multiple-stage antimalarial agent that inhibits protein synthesis,” 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 Winzeler, Susan A. Charman, Lidiya Bebrevska, David W. Gray, Simon Campbell, Alan H. Fairlamb, Paul Willis, Julian C. Rayner, David A. Fidock, Kevin D. Read, and Ian H. Gilbert; Nature, 522, 315-320, 18 June, 2015; doi:10.1038/nature14451
