KAI407, a potent non 8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro

23 Dec 2013

Anne-Marie  Zeeman,  Sandra  M.  van  Amsterdam,  Case  W.  McNamara, Annemarie Voorberg-van der Wel, Els J. Klooster, Alexander van den Berg, Edmond  J.  Remarque,  David  M.  Plouffe,  Geert-Jan  van  Gemert,  Adrian Luty, Robert Sauerwein, Kerstin Gagaring, Rachel Borboa, Zhong Chen, Kelli Kuhen, Richard J. Glynne, Arnab K. Chatterjee, Advait Nagle, Jason Roland,  Elizabeth  A.  Winzeler,  Didier  Leroy,  Brice  Campo,  Thierry  T. Diagana,  Bryan  K.  S.  Yeung,  Alan  W.  Thomas and  Clemens  H.  M. Kocken

Antimicrobial Agents and Chemotherapy



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 P. 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, stained with anti-Hsp70 antibodies and the relative proportion of small (hypnozoite) and large (schizont) forms relative to the untreated controls are counted. 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 tenfold dilutions (0.1, 1 and 10 μM final concentration). A novel compound, designated KAI407 showed an activity profile similar to primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (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 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 radical cure.

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