Targeting Plasmodium falciparum with purine antimetabolites as a therapeutic strategy

Abstract

<i>Plasmodium falciparum</i> lacks the <i>de novo</i> 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 <i>P. falciparum</i>, 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 <i>P. falciparum</i> Equilibrative Nucleoside Transporters (<i>Pf</i> ENTs) as conduits for therapeutic agents. Purine analogs that efficiently enter <i>P. falciparum</i>-infected erythrocytes, reach <i>Pf</i> ENTs, and undergo selective activation within the parasite can disrupt purine metabolism and nucleic acid synthesis, ultimately leading to parasite death. The <i>Pf</i> 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.