Malaria is a parasitic disease caused by Plasmodium species, which are spread by mosquitoes. The parasites enter the bloodstream through the mosquito’s saliva, then live in the liver to develop and reproduce. There are five Plasmodium species that can infect humans, including P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. The typical symptoms include fever, vomiting, and headaches. It can also develop into worse seizures, coma, and even death. Malaria widely distributes in tropical and subtropical areas, which is a malignant disease that caused 627,000 people to die in 2020. Therefore, finding cure methods for malaria has become a global issue.
Plasmepsins are aspartic acid proteases produced by P. falciparum. There are 10 coding genes, including Plm I, II, III, IV, V, VI, VII, IX, X, and HAP. Plasmepsins can catalyze the hydrolysis of the peptide bond in proteins and has hemoglobin-degrading activity. Thus, the enzyme family is the target for the treatment of malaria.
UCB7362 is an orally active and selective antimalarial Plasmepsin X inhibitor.
UCB7362 is more potent against Plm X than Plm IX with IC50s of 7 nM and 142 nM, respectively. In vivo experiments, UCB7362 (10-60 mg/kg, p.o.; twice a day, for 4 days) clears parasitemia from peripheral blood in a dose-dependent manner in P. falciparum-infected SCID mouse model. Besides, it also exhibits acceptable pharmacokinetic properties. In Sprague-Dawley rats, when administrate 1 mg/kg i.v., UCB7362 shows 43.9 mL/min/kg clearance and 793 nM·h AUC0-24; when administrate 10 mg/kg p.o., it exhibits an 11% oral availability and an AUC0-24 of 1410 nM·h.
In conclusion, UCB7362 is an orally active Plm X inhibitor with antimalarial activity and acceptable pharmacokinetic properties.