Drug repurposing: Teprenone modulates isoprenoid-dependent processes in Plasmodium falciparum and reduces the severity of experimental cerebral malaria

Resistance of Plasmodium to antimalarial drugs has become a major challenge, supporting the search for new compounds, drug repurposing, and the development of effective therapeutic combinations. One of the most severe complications of malaria is cerebral malaria, a neurological syndrome associated with coma, various permanent sequelae, and potentially fatal outcomes. Based on this, we evaluated the in vitro and in vivo antiplasmodial potential of a synthetic terpene known as teprenone (geranylgeranylacetone) against Plasmodium falciparum and Plasmodium berghei. Our results demonstrated that teprenone exhibited in vitro antiplasmodial activity against the 3D7 strain, with an IC₅₀ in the micromolar range. In addition, it exhibited low toxicity in HEP-G2 cells (human hepatocellular carcinoma) and a selectivity index greater than 10. Teprenone inhibited protein prenylation in P. falciparum in assays using radioactive FOH, reducing FPP incorporation into proteins, in addition to inhibiting GGOH transport in P. falciparum (3D7) cultures. In in vivo assays using a murine model of cerebral malaria, teprenone did not demonstrate efficacy in reducing parasitemia. Nevertheless, it had a beneficial effect in the treatment of cerebral malaria in C57BL/6 mice infected with P. berghei ANKA, increasing survival in the treated group compared with the control group. Treatment reduced IFN-γ levels in the brain, protected the blood–brain barrier from disruption, decreased leukocyte accumulation and the occurrence of microhemorrhages in the cerebral microvasculature. The results obtained in this study are expected to contribute to the development of new therapeutic strategies for cerebral malaria and encourage further investigations into the mechanism of action of teprenone.