Membrane-permeable 5-fluorodeoxyuridine triphosphate derivatives inhibit the proliferation of Plasmodium falciparum

Malaria tropica remains a major global health challenge, requiring new therapeutic strategies against Plasmodium falciparum . While nucleoside analogues are effective against viruses and cancer, their use against P. falciparum is limited by the parasite’s lack of nucleoside kinases. To overcome this, we tested cell-permeable derivatives of 5-fluorodeoxyuridine triphosphate (cpFdUTP) for anti-parasitic activity in infected human red blood cells. cpFdUTP rapidly and potently inhibited P. falciparum proliferation, arresting development at the trophozoite-to-schizont transition by stalling DNA replication, as revealed by a P. falciparum nuclear cycle sensor line. Although cpFdUTP also impaired human cell growth, supplementation with thymidine or cell-permeable deoxythymidine triphosphate (cpdTTP) selectively rescued human cells while maintaining P. falciparum inhibition. This identifies a potential therapeutic window for cpFdUTP in combination with thymidine, outlining a novel approach for malaria treatment.