Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents
Fig 5
WLW synergizes with multiple classes of structurally and functionally diverse antimalarials.
Isobolograms of WLW and (in descending order) DHA, OZ439, MB, b-AP15 and ESI tested on asynchronous parasites and highly synchronized rings and trophozoites. Cam3.II K13WT or Cam3.II K13C580Y parasites were exposed to compounds mixed at fixed ratios of their individual IC50 values (1:0, 4:1, 2:1, 1:1, 1:2, 1:4, 0:1). Asynchronous parasites were exposed for 72 hr and parasitemias were determined by flow cytometry. Highly synchronized rings (0–3 hr post-invasion) or trophozoites (tested 24 hr later) were exposed for 3 hr, followed by drug washouts and continued culture for 69 hr in drug-free media. Fractional IC50 (FIC50) values were plotted for each drug combination and fixed ratio and results were compared against a hypothetical isobole line illustrating a perfectly additive interaction (dashed line). Data show results of two independent isobologram assays (shown in different shades), each performed in duplicate, tested against Cam3.II K13WT (blue) and Cam3.II K13C580Y (red). Synergy is evidenced by individual FIC50 pairwise values falling below the dashed line of additive interactions (FIC50 = 1). DHA, dihydroartemisinin; ESI, eeyarestatin I; MB, methylene blue.