title: Targeting Plasmodium PI(4)K to eliminate malaria.
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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Case W
authors.initials: CW
authors.lastname: McNamara
authors.affiliation: Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Marcus Cs
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Novartis Institutes for Tropical Disease, 138670 Singapore.
authors.forename: Chek Shik
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Novartis Institutes for Tropical Disease, 138670 Singapore.
authors.forename: Siau Hoi
authors.initials: SH
authors.lastname: Lim
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Roland
authors.affiliation: Novartis Institutes for Tropical Disease, 138670 Singapore.
authors.forename: Oliver
authors.initials: O
authors.lastname: Simon
authors.affiliation: Novartis Institutes for Tropical Disease, 138670 Singapore.
authors.forename: Bryan Ks
authors.initials: BK
authors.lastname: Yeung
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: McCormack
authors.affiliation: Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Manary
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.affiliation: TropIQ Health Sciences, Nijmegen, The Netherlands.
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Dechering
authors.affiliation: Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Tr Santha
authors.initials: TS
authors.lastname: Kumar
authors.affiliation: Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Philipp P
authors.initials: PP
authors.lastname: Henrich
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Ibanez
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Kuhen
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fischli
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland.|University of Basel, CH-4003 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Plouffe
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.affiliation: Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts 02118, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Rameh
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Trappe
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Haasen
authors.affiliation: TropIQ Health Sciences, Nijmegen, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Timmerman
authors.affiliation: TropIQ Health Sciences, Nijmegen, The Netherlands.|Department of Medical Microbiology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.affiliation: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (ASTAR), Biopolis, Singapore.
authors.forename: Rossarin
authors.initials: R
authors.lastname: Suwanarusk
authors.affiliation: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (ASTAR), Biopolis, Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore.
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.affiliation: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (ASTAR), Biopolis, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Clemens Hm
authors.initials: CH
authors.lastname: Kocken
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.affiliation: Novartis Institutes for Tropical Disease, 138670 Singapore.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bodenreider
authors.affiliation: Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Novartis Institutes for Tropical Disease, 138670 Singapore.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.|Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D048749:Cytokinesis / Q000187:drug effects; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000469:parasitology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008018:Life Cycle Stages / Q000187:drug effects; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology*; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010961:Plasmodium / Q000145:classification / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology; D015203:Reproducibility of Results; D052939:Schizonts / Q000166:cytology / Q000187:drug effects; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D019870:1-Phosphatidylinositol 4-Kinase; D000255:Adenosine Triphosphate; D005227:Fatty Acids; D007093:Imidazoles; D018129:Phosphatidylinositol Phosphates; D011720:Pyrazoles; D011810:Quinoxalines; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C037178:phosphatidylinositol 4-phosphate