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 parasites 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/640175v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b20ddaorg.highwire.dtl.DTLVardef@1ab6497org.highwire.dtl.DTLVardef@15932e2org.highwire.dtl.DTLVardef@11b9e61_HPS_FORMAT_FIGEXP M_FIG C_FIG