Antimalarial activity of human immunodeficiency virus type 1 protease inhibitors

Abstract

Aspartic proteases play key roles in the biology of malaria parasites and human immunodeficiency virus type 1 (HIV-1). We tested the activity of seven HIV-1 protease inhibitors against cultured Plasmodium falciparum. All compounds inhibited the development of parasites at pharmacologically relevant concentrations. The most potent compound, lopinavir, was active against parasites (50% inhibitory concentration [IC50], 0.9 to 2.1 microM) at concentrations well below those achieved by ritonavir-boosted lopinavir therapy. Lopinavir also inhibited the P. falciparum aspartic protease plasmepsin II at a similar concentration (IC50, 2.7 microM). These findings suggest that use of HIV-1 protease inhibitors may offer clinically relevant antimalarial activity.

FIG. 1.

Effects of HIV-protease inhibitors on cultured parasites. A. Parasite morphology. Synchronized ring stage parasites were incubated with 10 μM lopinavir. Treated and control (with equivalent concentrations of DMSO) parasites were evaluated at the indicated time points on Giemsa-stained smears. B. Parasite development. Synchronized parasites were incubated with multiple concentrations of lopinavir, beginning at the ring stage. After 48 h, ring parasitemias were determined by flow cytometry analysis of YOYO-1-stained parasites, as previously described (11). Results represent two independent experiments, each performed in duplicate using the HB3 strain of P. falciparum. Error bars represent standard deviations.