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

The urgent need for original 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 inhibitory effects on Plasmodium parasites. It blocks the active exit process, named egress, of merozoites and gametes from infected erythrocytes. UA2239 disrupts the essential cyclic guanosine monophosphate (cGMP)-dependent egress pathway by decreasing cGMP levels in the parasite, strongly suggesting Plasmodium falciparum guanylyl cyclase α as its primary target. We also uncovered remarkable molecular mechanisms of resistance developed by parasites after prolonged exposure to the drug, which involve mutating not the target itself, but downstream effectors. The unique mechanism of action of UA2239 makes it a valuable first-in-class candidate for further development. Its ability to inhibit both parasite growth and transmission highlights its therapeutic potential as a dual-stage antimalarial agent.