PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites

ABSTRACTTwo PlasmodiumPI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivotesting as causal prophylactic and radical-cure agents for Plasmodium cynomolgisporozoite-infected rhesus macaques, based on their in vitroactivity against liver stages. Animals were infected with P. cynomolgisporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. 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 was sufficient to achieve efficacy based on our in vitrodata. These findings indicate that PlasmodiumPI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitroculture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo.