Malaria is a parasitic disease caused by Plasmodium species, which are spread by mosquitoes. Erythrocytes are the replicating factories for malaria parasites. There are three malarial life-cycle stages: exoerythrocytic forms, asexual blood stages, and transmission stages. Nowadays, Malaria is still a threatening cause of death worldwide. Malaria widely distributes in tropical and subtropical areas, which is a malignant disease that caused 627,000 people to die in 2020. Chemotherapeutic antimalarial drugs usually target aspartic proteases. But how to overcome the problem of drug resistance is a growing problem.
Plasmepsin IX and plasmepsin X are key aspartic proteases for controlling malaria parasite egress and invasion of erythrocytes. Specifically, plasmepsin IX and plasmepsin X play a critical role in the red blood cell stages. Therefore, inhibition of Plasmepsin IX/X is a potential antimalarial strategy.
WM382 is a potent and orally active plasmepsin IX/X inhibitor across the parasite life cycle.
WM382 effectively inhibits plasmepsin IX/X with IC50 values of 1.4 nM and 0.03 nM, respectively. Furthermore, WM382 binds plasmepsin X with high affinity (Ki: 0.035 nM). WM382 also inhibits P. falciparum and P. knowlesi growth (EC50s: 0.6 nM and 0.2 nM, respectively). Importantly, pre-existing resistance mutations in drug-resistant parasites have no effect on the potency of WM382. Besides, WM382 (20 mg/kg twice daily or 1-30 mg/kg once daily, p.o., for 4 d) is able to clear parasites in P. berghei and P. falciparum blood infection mice model. WM382 also blocks transmission of P. falciparum gametocytes to mosquitoes. WM382 is also efficacious against P. falciparum asexual infection in humanized mice.
In conclusion, WM382 is a highly potent and orally active dual plasmepsin IX/X inhibitor with antimalarial activity both in vitro and in vivo, and shows an excellent resistance profile.