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PI4K is a prophylactic, but not radical curative target in Plasmodium vivax-type malaria parasites

Zeeman, Anne-Marie and Lakshminarayana, Suresh Bangalore and van der Werff, Nicole and Klooster, Els and Kondreddi, Ravinder Reddy and Bodenreider, Christophe and Simon, Oliver and Sauerwein, Robert and Yeung, Bryan King Sing and Diagana, Thierry Tidiane and Kocken, Clemens (2016) PI4K is a prophylactic, but not radical curative target in Plasmodium vivax-type malaria parasites. Antimicrobial Agents and Chemotherapy (AAC) .

Abstract

Two Plasmodium PI4 kinase inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical cure agents of P. 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 KDU691 and LMV599 compounds were fully protective when administered prophylactically and the more potent compound LMV599 achieved protection as a single oral 25 mg/kg dose. 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 were 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 compounds activity on established hypnozoites and predict radical cure in vivo.

Item Type: Article
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27791

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