Biology subjects

Dobrescu, I.

Publications and source records attributed to Dobrescu, I..

2 recordsLinked to original sources

bioRxiv2022

Quinazoline-quinoline bisubstrate inhibitors target eukaryotic translation initiation factor 3 in Plasmodium falciparum

Malaria drug resistance is hampering the fight against the deadliest parasitic disease affecting over 200 million people worldwide. We recently developed quinoline-quinazoline-based inhibitors (as compound 70) as promising new antimalarials. Here we aimed to investigate their mechanism of action by using Thermal Proteome Profiling (TPP). The eukaryotic translation initiation factor 3 (EIF3i) subunit I was identified as the main target of the inhibitor in P. falciparum. This protein is not a known drug target in malaria parasites. P. falciparum parasite lines were generated expressing either a HA tag or an inducible knockdown of the PfEIF3i gene to further characterize the target protein. PfEIF3i was stabilized in presence of the compound 70 in a cellular thermal shift-western blot assay, confirming that PfEIF3i is a target of quinoline-quinazoline-based inhibitors. In addition, PfEIF3i-inducible knock-down blocks intra-erythrocytic development in the trophozoite stage indicating that it has a vital function. We show that PfEIF3i is mostly expressed in late intraerythrocytic stages and localizes in the cytoplasm. Previous mass spectrometry reports show that EIF3i is expressed in all parasite life cycle stages. Hence, quinoline-quinazoline-based inhibitors allowed to identify PfEIF3i as a valuable target for the design of new antimalarial drugs active all along the life cycle of the parasite.

pharmacology and toxicology↗

bioRxiv2022

Hemisynthetic derivatives of the natural alkaloid trilobine are fast-acting antimalarial compounds with sustained activity in multi-drug resistant P. falciparum isolates

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 hirsutus. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed us to identify compound 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 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. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down strategy to identify potential protein targets of this chemical family. Mass spectrometry analysis identified the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms.

pathology↗