Importin alpha inhibitors act against the differentiated stages of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii
Protozoan parasites of the phylum Apicomplexa, including Plasmodium falciparum and Toxoplasma gondii, cause widespread disease in humans. New drugs and protein targets are required for the treatment of these diseases, particularly therapies targeting multiple stages of the parasite life cycles. Nuclear import, carried out by the transporters importin (IMP) and {beta} subunits, is a valid target for the discovery of lead compounds against these protozoan parasites: small molecules were identified that inhibit interactions between IMP and nuclear localisation signals in vitro and also inhibit the growth of the rapidly-dividing stages of P. falciparum and T. gondii (asexual stages and tachyzoites) in culture. In this report, we add another small molecule (Bay 11-7082) to the panel of inhibitors of IMP and test the ability of these inhibitors to first, inhibit nuclear transport in the rapidly dividing stages and, next, the maturation of differentiated stages of both parasites. We show that GW5074 and CAPE inhibit nuclear transport in the P. falciparum blood stages, while Bay 11-7085 inhibits nuclear transport in T. gondii tachyzoites. Interestingly, CAPE strongly inhibits gametocyte maturation, the sexual stages of P. falciparum, and Bay 11-7085 weakly inhibits bradyzoite differentiation, the latent stages of T. gondii. As differentiation of both these stages is dependent on activation of gene expression, triggered by the nuclear translocation of transcription factors, our work provides a "proof of concept" that targeting nuclear import is a viable strategy for the development of therapeutics against multiple stages of apicomplexan parasites, some of them recalcitrant to existing drugs.