Drug-target of DNA methyltransferase inhibitors

Malaria eradication requires the development of new drugs to combat drug-resistant parasites. The search for new chemical scaffolds that target novel pathways of the human malaria parasite Plasmodium falciparum is of highest priority. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus sp. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivates allowed us to identify compound 84 (c-84) that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Efforts were made to obtain compounds with significantly improved preclinical properties. Out of those, compound 125 (c-125) delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays) and in vivo using membrane feeding assay in the Anopheles stephensi vector. C-125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down to identify potential protein targets of this chemical family. Our mass spectrometry analysis identified the parasite interactome with trilobine alkaloid, allowing us to identify protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms in malaria parasites.