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KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2014; Vol. 58 (3), pp. 1586-95. Date of Electronic Publication: 2013 Dec 23. - Publication Year :
- 2014
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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.
- Subjects :
- Animals
Antimalarials therapeutic use
Drug Evaluation, Preclinical methods
Female
Hepatocytes parasitology
Imidazoles therapeutic use
In Vitro Techniques
Liver parasitology
Macaca mulatta parasitology
Malaria parasitology
Malaria prevention & control
Mice
Mice, Inbred ICR
Pyrazines therapeutic use
Sporozoites drug effects
Antimalarials pharmacology
Imidazoles pharmacology
Malaria drug therapy
Plasmodium cynomolgi drug effects
Pyrazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 58
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 24366744
- Full Text :
- https://doi.org/10.1128/AAC.01927-13