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Targeting Plasmodium PI(4)K to eliminate malaria

McNamara, Case W. and Lee, Marcus C. S. and Lim, Chek Shik and Lim, Siau Hoi and Roland, Jason and Nagle, Advait and Simon, Oliver and Yeung, Bryan K. S. and Chatterjee, Arnab K. and McCormack, Susan L. and Manary, Micah J. and Zeeman, Anne-Marie and Dechering, Koen J. and Kumar, T. R. Santha and Henrich, Philipp P. and Gagaring, Kerstin and Ibanez, Maureen and Kato, Nobutaka and Kuhen, Kelli L. and Fischli, Christoph and Rottmann, Matthias and Plouffe, David M. and Bursulaya, Badry and Meister, Stephan and Rameh, Lucia and Trappe, Joerg and Haasen, Dorothea and Timmerman, Martijn and Sauerwein, Robert W. and Suwanarusk, Rossarin and Russell, Bruce and Renia, Laurent and Nosten, Francois and Tully, David C. and Kocken, Clemens H. M. and Glynne, Richard J. and Bodenreider, Christophe and Fidock, David A. and Diagana, Thierry T. and Winzeler, Elizabeth A.. (2013) Targeting Plasmodium PI(4)K to eliminate malaria. Nature, Vol. 504, H. 7479. pp. 248-253.

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Official URL: http://edoc.unibas.ch/dok/A6211918

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Abstract

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Macmillan
ISSN:0028-0836
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:29 Jan 2016 07:59
Deposited On:25 Apr 2014 08:01

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