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Title: Targeting Plasmodium PI(4)K to eliminate malaria
Authors: 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
Elizabeth A. Winzeler
The Genomics Institute of the Novartis Research Foundation
Columbia University Medical Center
Novartis Institutes for Tropical Disease
University of California, San Diego
Biomedical Primate Research Centre - Rijswijk
TropIQ Health Sciences
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
Boston University School of Medicine
Novartis International AG
Radboud University Nijmegen Medical Centre
Agency for Science, Technology and Research, Singapore
Yong Loo Lin School of Medicine
Nuffield Department of Clinical Medicine
Mahidol University
Keywords: Multidisciplinary
Issue Date: 29-Nov-2013
Citation: Nature. Vol.504, No.7479 (2013), 248-253
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. © 2013 Macmillan Publishers Limited. All rights reserved.
ISSN: 14764687
Appears in Collections:Scopus 2011-2015

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