Figure 2. Binding affinity and cellular potency of XL888 and BX-2819.
(A-B) Binding plots for XL888 (A) and BX-2819 (B) demonstrating their dose-dependent displacement of the FITC-GA tracer to PfHsp90 (orange) and HsHsp90 (blue). For XL888 (A), competitive binding curves calculate an apparent Ki = 27 ± 7.8 nM for PfHsp90 compared to Ki = 130 ± 30 nM for HsHsp90 (p = 0.0032). For BX-2819 (B), competitive binding curves calculate an apparent Ki = 24 ± 4.4 nM for PfHsp90 compared to Ki = 49 ± 4.3 nM for HsHsp90 (p = 0.0114). Data shown as means ± SEM, n ≥ 4; unpaired t-test. (C-D) Dose-response curves for XL888 (blue) and BX-2819 (orange) inhibition of P. falciparum blood stage parasites (C), yielding EC50s of 0.33 ± 0.11 μM and 0.74 ± 0.034 μM, respectively, as well as P. berghei liver stage parasites (D), yielding EC50s of 0.24 ± 0.045 μM and 1.5 ± 0.41 μM, respectively. Data shown as means ± SEM, n ≥ 2. (E) The PfHsp90 inhibitors BX-2819 (BX; 500 nM), XL888 (XL; 200 nM), and geldanamycin (GA; 300 nM) slow parasite progression through their erythrocytic cycle when treated at the ring stage (~12 hours post invasion) compared to treatment with DMSO. (F) Early and late P. falciparum gametocyte viability is decreased by geldanamycin (GA) at 1 μM and 10 μM compared to the DMSO control. Data shown as means ± SEM, n = 3. *<0.05, **<0.01, ****<0.0001; two-way ANOVA, Tukey’s multiple comparison.