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Nature. 2013 Dec 12;504(7479):248-253. doi: 10.1038/nature12782. Epub 2013 Nov 27.

Targeting Plasmodium PI(4)K to eliminate malaria.

Author information

1
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
2
Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA.
3
Novartis Institutes for Tropical Disease, 138670 Singapore.
4
Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
5
Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
6
TropIQ Health Sciences, Nijmegen, The Netherlands.
7
Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland.
8
University of Basel, CH-4003 Basel, Switzerland.
9
Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts 02118, USA.
10
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
11
Department of Medical Microbiology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands.
12
Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (ASTAR), Biopolis, Singapore.
13
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore.
14
Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
15
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
16
Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
#
Contributed equally

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.

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PMID:
24284631
PMCID:
PMC3940870
DOI:
10.1038/nature12782
[Indexed for MEDLINE]
Free PMC Article

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