Dual-targeting proteasome inhibitor ONX-0914 demonstrates potent antiplasmodial activity for malaria treatment.

There is an urgent need to discover novel antimalarial drugs that are safe and provide effective cures with broad therapeutic potential, novel mechanisms of action, and suitable pharmacokinetic profiles. We studied ONX-0914, which targets the proteolytic system of eukaryotic cells and has been effective against cancer and immune disorders. The antiplasmodial activity and safety of ONX-0914 were investigated both in vitro and in vivo, along with its mechanism of action and potential bioavailability. Notably, ONX-0914 strongly inhibited the proliferation of various Plasmodium falciparum strains, including chloroquine (CQ)- and artesunate (ART)-sensitive and -resistant strains, with a low nanomolar IC50 (<50nM). It also exhibited potent synergistic activity with ART, blocking the proliferation of ART- and CQ-resistant strains, while showing low toxicity to human cells (CC50 > 100 μM). The potent antiplasmodial activity of ONX-0914 is attributed to the dual inhibition of haemoglobin metabolism and the ubiquitin‒proteasome system. In vivo results revealed that ONX-0914 suppressed P. berghei ANKA parasites by > 95 % after 4 days of treatment and increased survival rate and mean survival time following a single dose administered via various routes (effect dose ED50 of 7.62 mg/kg per oral [PO] and 6.52 mg/kg intraperitoneal [IP], and intravenous [IV]). ONX-0914 treatment resulted in a low recrudescence rate after one month (<2 %), reduced organ lesions (brain, heart, lung, liver, spleen, and kidney) compared to untreated controls, and favourable pharmacokinetic parameters (AUC >20,960 h∗μg/ml, T1/2 = 7.9 h [IV], 0.7 h [PO], C max = 10708.2 μg/ml [PO], bioavailability = 23.83 %), supporting its antimalarial efficacy. Owing to its low toxicity, robust antiplasmodial activity through a combination mechanism, and supportive pharmacokinetic properties, ONX-0914 is a promising antimalarial agent.