Antimalarial asexual stage-specific and gametocytocidal activities of HIV protease inhibitors

Abstract

The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum. While darunavir demonstrated limited antimalarial activity (effective concentration [EC(50)], >50 microM), tipranavir was active at clinically relevant concentrations (EC(50), 12 to 21 microM). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.

FIG. 1.

In vitro stage-specific activities of PIs against P. falciparum asexual parasites. Erythrocytes infected with P. falciparum line D10 at ring (filled circles) trophozoite (open circles), or schizont (filled squares) stages were exposed to saquinavir (SQV; 40 μM), tipranavir (TPV; 150 μM), lopinavir (LPV; 20 μM), and chloroquine (CHQ; 50 nM) for 1, 2, 4, 6, or 8 h, as described in the text. Data are presented as percent growth inhibition (+SE) compared to vehicle controls (taken as 100% growth). Each assay was repeated twice in triplicate.

FIG. 2.

Activities of selected PIs in gametocyte and gametocyte induction inhibition assays. (A) In vitro antigametocytogenesis activities of selected PIs as determined using transgenic Pfs16-GFP P. falciparum parasites. (B) Activities of PIs against Pfs16-GFP P. falciparum gametocytes. All drugs were assessed at their EC₁₀, EC₅₀, and EC₉₀ values as determined by [³H]hypoxanthine incorporation against asexually replicating parasites. Bars with * indicate significant changes compared to vehicle control wells (P < 0.01). Pfs16-GFP gametocytes, unlike Pfs16-GFP asexual-stage parasites, express GFP-tagged Pfs16 (3).