Browsing by Author "Novartis Institutes for Tropical Disease"

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    Targeting Plasmodium PI(4)K to eliminate malaria
    (2013-11-29) 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
    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.