Publication:
Targeting Plasmodium PI(4)K to eliminate malaria

Issued Date

2013-11-29

Resource Type

Article

ISSN

14764687
00280836

DOI

10.1038/nature12782

Other identifier(s)

2-s2.0-84890428942

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Nature. Vol.504, No.7479 (2013), 248-253

Suggested Citation

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 Targeting Plasmodium PI(4)K to eliminate malaria. Nature. Vol.504, No.7479 (2013), 248-253. doi:10.1038/nature12782 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/32815

Research Projects

Organizational Units

Authors

Journal Issue

Thesis

Title

Targeting Plasmodium PI(4)K to eliminate malaria

Author(s)

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

Other Contributor(s)

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

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.

Keyword(s)

Multidisciplinary

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/32815

Collections

Scopus 2011-2015