An acyclic nucleoside phosphonate effectively blocks the egress of the malaria parasite by inhibiting the synthesis of cyclic GMP

The urgent need for new antimalarial therapies arises from the alarming spread of malaria parasite resistance to existing drugs. A promising candidate, UA2239, an acyclic nucleoside phosphonate with a guanine as nucleobase, demonstrates rapid and irreversible cytotoxic effects on Plasmodium parasites, both in vitro and in an animal model. It blocks the active exit process, named egress, of merozoites and gametes from infected erythrocytes. Interestingly, while mutations in the cyclic GMP-dependent protein kinase (PKG) were identified in UA2239-resistant P. falciparum lines, PKG is not the direct target of UA2239. UA2239 disrupts the essential cGMP-dependent egress pathway by decreasing cGMP levels in the parasite, making guanylate cyclase ( Pf GCα) the most likely primary target. This unique mechanism of action makes UA2239 a valuable first-in-class candidate for further development. Additionally, its ability to inhibit both parasite growth and transmission highlights its therapeutic potential as a dual-stage antimalarial agent.