Targeting Plasmodium falciparum with purine antimetabolites as a therapeutic strategy

Plasmodium falciparum lacks the de novo purine biosynthesis pathway and relies exclusively on salvaging free purines from the host to meet its metabolic requirements. This absolute dependence on the purine salvage pathway provides a compelling opportunity for antimalarial drug development, particularly in the face of rising resistance to current therapies. Although the purine salvage system has been extensively studied as a potential drug target in P. falciparum, no purine-based antimalarial drug has yet reached clinical use. In this review, we summarize the potential of targeting the purine salvage pathway in antimalarial drug development, with a focus on strategies that leverage P. falciparum Equilibrative Nucleoside Transporters (Pf ENTs) as conduits for therapeutic agents. Purine analogs that efficiently enter P. falciparum-infected erythrocytes, reach Pf ENTs, and undergo selective activation within the parasite can disrupt purine metabolism and nucleic acid synthesis, ultimately leading to parasite death. The Pf ENTs therefore offer a unique and viable route for delivering purine-based analogs into the parasite. Such approaches provide a framework for target-based design of purine-analog-based antimalarial therapies.