title: PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites.
abstract: Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical-cure agents for Plasmodium cynomolgi sporozoite-infected rhesus macaques, based on their in vitro activity against liver stages. Animals were infected with P. cynomolgi sporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our in vitro data. These findings indicate that Plasmodium PI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitro culture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo.
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: van der Werff
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands.
authors.forename: Els J
authors.initials: EJ
authors.lastname: Klooster
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Voorberg-van der Wel
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Ravinder R
authors.initials: RR
authors.lastname: Kondreddi
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bodenreider
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Oliver
authors.initials: O
authors.lastname: Simon
authors.affiliation: Medical Parasitology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore thierry.diagana@novartis.com kocken@bprc.nl.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands thierry.diagana@novartis.com kocken@bprc.nl.
authors.forename: Clemens H M
authors.initials: CH
authors.lastname: Kocken
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D008253:Macaca mulatta; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000469:parasitology*; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010966:Plasmodium vivax / Q000187:drug effects / Q000472:pathogenicity*; D034101:Sporozoites / Q000187:drug effects
chemical_list: D000962:Antimalarials