Infectious disease

Cell culture and mouse studies identified an inhibitor of P. falciparum proteasome subunit β type 2 and proteasome subunit β type 5 that could help treat malaria. Chemical synthesis and testing of vinyl sulfone peptides in human erythrocyte cell-based P. falciparum replication assays, followed by optimization of hits yielded a compound that inhibited parasite replication with an EC₅₀ of 19 nM. In vitro, the compound inhibited the P. falciparum β type 2 and β type 5 proteasome subunits with IC₅₀ values of 7.05 and 0.94 μM, respectively. In cultures of artemisinin-sensitive or -resistant P. falciparum strains, the compound plus the antimalarial drug dihydroartemisinin decreased growth compared with either agent alone. In a mouse model of P. berghei-induced malaria, daily IV 50 mg/kg doses of the compound decreased parasitemia compared with vehicle. Next steps could include optimizing the compound for oral bioavailability...