Targeting Plasmodium PI(4)K to eliminate malaria

TY - JOUR

T1 - Targeting Plasmodium PI(4)K to eliminate malaria

AU - McNamara, Case W.

AU - Lee, Marcus C.S.

AU - Lim, Chek Shik

AU - Lim, Siau Hoi

AU - Roland, Jason

AU - Nagle, Advait

AU - Simon, Oliver

AU - Yeung, Bryan K.S.

AU - Chatterjee, Arnab K.

AU - McCormack, Susan L.

AU - Manary, Micah J.

AU - Zeeman, Anne-Marie

AU - Dechering, Koen J.

AU - Kumar, T. R.Santha

AU - Henrich, Philipp P.

AU - Gagaring, Kerstin

AU - Ibanez, Maureen

AU - Kato, Nobutaka

AU - Kuhen, Kelli L.

AU - Fischli, Christoph

AU - Rottmann, Matthias

AU - Plouffe, David M.

AU - Bursulaya, Badry

AU - Meister, Stephan

AU - Rameh, Lucia

AU - Trappe, Joerg

AU - Haasen, Dorothea

AU - Timmerman, Martijn

AU - Sauerwein, Robert W.

AU - Suwanarusk, Rossarin

AU - Russell, Bruce

AU - Renia, Laurent

AU - Nosten, Francois

AU - Tully, David C.

AU - Kocken, Clemens H.M.

AU - Glynne, Richard J.

AU - Bodenreider, Christophe

AU - Fidock, David A.

AU - Diagana, Thierry T.

AU - Winzeler, Elizabeth A.

N1 - Funding Information: Acknowledgements We thank E. Miller for critical review of the manuscript and figure design. We also thank A. Rodriguez and the insectary core facility team at New York University for reliable supplies of malaria-infected mosquitoes. We gratefully acknowledge translational research grants (WT078285 and WT096157) from the Wellcome Trust and funding from the Medicines for Malaria Venture (MMV) to the Genomics Institute of the Novartis Research Foundation, the Swiss Tropical and Public Health Institute, Columbia University, the Novartis Institute for Tropical Diseases, the Singapore Immunology Network and Horizontal Programme on Infectious Diseases under the Agency Science Technology and Research (A*STAR, Singapore), and the Wellcome Trust (UK). Shoklo Malaria Research Unit is sponsored by The Wellcome Trust (UK), as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust-Mahidol University. E.A.W. and D.A.F. are supported by grants from the Bill and Melinda Gates Foundation, MMV, and the National Institutes of Health (R01AI090141 to E.A.W. and R01085584 and R01079709 to D.A.F.).

PY - 2013/11/27

Y1 - 2013/11/27

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84890428942

U2 - 10.1038/nature12782

DO - 10.1038/nature12782

M3 - Article

C2 - 24284631

AN - SCOPUS:84890428942

SN - 0028-0836

VL - 504

SP - 248

EP - 253

JO - Nature

JF - Nature

IS - 7479

ER -