title: KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.
abstract: Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure.
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.forename: Sandra M
authors.initials: SM
authors.lastname: van Amsterdam
authors.forename: Case W
authors.initials: CW
authors.lastname: McNamara
authors.forename: Annemarie
authors.initials: A
authors.lastname: Voorberg-van der Wel
authors.forename: Els J
authors.initials: EJ
authors.lastname: Klooster
authors.forename: Alexander
authors.initials: A
authors.lastname: van den Berg
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Remarque
authors.forename: David M
authors.initials: DM
authors.lastname: Plouffe
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.forename: Adrian
authors.initials: A
authors.lastname: Luty
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Jason
authors.initials: J
authors.lastname: Roland
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.forename: Alan W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Clemens H M
authors.initials: CH
authors.lastname: Kocken
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D022781:Hepatocytes / Q000469:parasitology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008099:Liver / Q000469:parasitology; D008253:Macaca mulatta / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology / Q000517:prevention & control; D051379:Mice; D008813:Mice, Inbred ICR; D016789:Plasmodium cynomolgi / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D034101:Sporozoites / Q000187:drug effects
chemical_list: D000962:Antimalarials; D007093:Imidazoles; C000592661:KAI407; D011719:Pyrazines