Abstact

BACKGROUND: The global burden of malaria remains substantial, and increasing parasite resistance to current antimalarials necessitates the development of drugs with unique mechanisms of action. This study aimed to develop and characterise a new antimalarial compound targeting Plasmodium aspartic proteases. METHODS: We conducted high-throughput screening, medicinal chemistry optimisation, and extensive in vitro and in vivo testing to develop and evaluate MK-7602, a dual inhibitor of plasmepsins IX and X. FINDINGS: MK-7602, a clinical candidate, acts as a dual sub-nanomolar inhibitor of plasmepsins IX and X in multiple Plasmodium species. It exhibits favourable pharmacokinetic properties and a promising safety profile. MK-7602 demonstrates activity against liver and blood life-cycle stages of the parasite and blocks transmission to mosquitoes. Importantly, it shows a high barrier to resistance development and lacks cross-resistance with Plasmodium falciparum strains resistant to other antimalarials. MK-7602 effectively inhibits both wild-type parasites and those with increased plasmepsin expression, highlighting its potential to overcome existing resistance mechanisms. INTERPRETATION: MK-7602 represents a new class of antimalarial for treating uncomplicated malaria with a new mechanism of action and the potential to address drug-resistant malaria. Clinical evaluation of MK-7602's activity against P. falciparum is ongoing. FUNDING: This work was funded by The Wellcome Trust (109662/Z/15/Z, 202749/Z/16/Z, 219658/Z/19/Z), NHMRC (GNT1176955, GNT637406, GNT1173049), the Human Frontiers Science Program (LT0001/2022-L, JMD), Drakensberg Trust, the Victorian State Government Operational Infrastructure Support grant, and the Australian Government NHMRC IRIISS. JPo was supported by the NIH/NIAID (R01AI173171, R01AI175134 and R61AI187100) and the Pasteur International Unit PvESMEE.