Diagana, Thierry Tidiane, Mcnamara, Case, Roland, Jason, Nagle, Advait, Yeung, Bryan King Sing, Zeeman, Anne-Marie, Winzeler, Elizabeth, Plouffe, David and Kocken, Clemens (2014) KAI407, a potent non 8-aminoquinoline compound that kills Plasmodium cynomolgi dormant liver stage parasites in vitro. Antimicrobial Agents and Chemotherapy.

Abstract

Abstract
A new compound with potential radical cure antimalarial activity was identified using a low throughput assay with in vitro cultured Plasmodium cynomolgi hypnozoite-forms. In this assay primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exooerythrocytic development is monitored in the presence of compounds. After 6 days of culturing, the liver stage cultures are fixed and stained with anti-Hsp70 antibodies and the relative proportion of small (hypnozoite) and large (schizont) forms relative to the untreated control 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 concentrations). A novel compound, designated KAI407 showed a profile similar to primaquine, efficiently killing both in vitro cultured developing liver stages and hypnozoite-forms (IC50 for small stages: were 0.69 µM (KAI407) and 0.84 µM (PQ); for developing liver stages: 0.64 µM (KAI407) and 0.37 µM (PQ)). 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 radical cure of P. vivax malaria.

Item Type:	Article
Date Deposited:	27 Apr 2016 23:45
Last Modified:	27 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/10017