Targeting Plasmodium PI(4)K to eliminate malaria

Case W. McNamara, Marcus C. S. Lee, Chek Shik Lim, Siau Hoi Lim, Jason Roland, Advait Nagle, Oliver Simon, Bryan K. S. Yeung, Arnab K. Chatterjee, Susan L. McCormack, Micah J. Manary, Anne-Marie Zeeman, Koen J. Dechering, T. R. Santha Kumar, Philipp P. Henrich, Kerstin Gagaring, Maureen Ibanez, Nobutaka Kato, Kelli L. Kuhen, Christoph Fischli, Matthias Rottmann, David M. Plouffe, Badry Bursulaya, Stephan Meister, Lucia Rameh, Joerg Trappe, Dorothea Haasen, Martijn Timmerman, Robert W. Sauerwein, Rossarin Suwanarusk, Bruce Russell, Laurent Renia, Francois Nosten, David C. Tully, Clemens H. M. Kocken, Richard J. Glynne, Christophe Bodenreider, David A. Fidock, Thierry T. Diagana () and Elizabeth A. Winzeler ()
Additional contact information
Case W. McNamara: Genomics Institute of the Novartis Research Foundation
Marcus C. S. Lee: Columbia University Medical Center
Chek Shik Lim: Novartis Institutes for Tropical Disease, 138670 Singapore
Siau Hoi Lim: Novartis Institutes for Tropical Disease, 138670 Singapore
Jason Roland: Genomics Institute of the Novartis Research Foundation
Advait Nagle: Genomics Institute of the Novartis Research Foundation
Oliver Simon: Novartis Institutes for Tropical Disease, 138670 Singapore
Bryan K. S. Yeung: Novartis Institutes for Tropical Disease, 138670 Singapore
Arnab K. Chatterjee: Genomics Institute of the Novartis Research Foundation
Susan L. McCormack: Genomics Institute of the Novartis Research Foundation
Micah J. Manary: School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
Anne-Marie Zeeman: Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands
Koen J. Dechering: TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands
T. R. Santha Kumar: Columbia University Medical Center
Philipp P. Henrich: Columbia University Medical Center
Kerstin Gagaring: Genomics Institute of the Novartis Research Foundation
Maureen Ibanez: Genomics Institute of the Novartis Research Foundation
Nobutaka Kato: Genomics Institute of the Novartis Research Foundation
Kelli L. Kuhen: Genomics Institute of the Novartis Research Foundation
Christoph Fischli: Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland
Matthias Rottmann: Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland
David M. Plouffe: Genomics Institute of the Novartis Research Foundation
Badry Bursulaya: Genomics Institute of the Novartis Research Foundation
Stephan Meister: School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
Lucia Rameh: School of Medicine, Boston University
Joerg Trappe: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland
Dorothea Haasen: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland
Martijn Timmerman: TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands
Robert W. Sauerwein: TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands
Rossarin Suwanarusk: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore
Bruce Russell: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore
Laurent Renia: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore
Francois Nosten: Centre for Tropical Medicine, University of Oxford, Oxford OX3 7BN, UK
David C. Tully: Genomics Institute of the Novartis Research Foundation
Clemens H. M. Kocken: Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands
Richard J. Glynne: Genomics Institute of the Novartis Research Foundation
Christophe Bodenreider: Novartis Institutes for Tropical Disease, 138670 Singapore
David A. Fidock: Columbia University Medical Center
Thierry T. Diagana: Novartis Institutes for Tropical Disease, 138670 Singapore
Elizabeth A. Winzeler: Genomics Institute of the Novartis Research Foundation

Nature, 2013, vol. 504, issue 7479, 248-253

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12782

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