Discovery of dual plasmepsin-targeting antimalarial agents that disrupt multiple stages of the malaria parasite lifecycle

The imino pyrimidinones are a novel drug class that inhibit P. falciparum. The compound WM382 potently inhibits the aspartyl proteases Plasmepsin IX (PMIX) and PMX in multiple Plasmodium spp., with an excellent safety profile in humans and a high barrier to drug resistance. In vivo, WM382 was orally available and cured mice of P. berghei asexual infection and prevented transition from liver to blood after sporozoite infection. WM382 was additionally curative of P. falciparum asexual infection in humanized mice and prevented gametocyte transmission to mosquitoes. Using WM382 and an intermediate compound WM4, we show that PMX is autocatalytic and a master activator of merozoite invasion through activation of the sheddase subtilisin 2 (SUB2) and direct maturation of multiple proteins required for invasion, development and egress. The imino pyrimidinones are a promising new antimalarial drug class well suited for advancement to clinical trials.