Development and biological characterization of dual-targeting inhibitors against the apicomplexan parasite Plasmodium falciparum – DualTargApi

Plasmodium falciparum, a protozoan pathogen, is still the greatest threat causing malaria with severe clinical significance and negative socio economic impact. This parasite possesses a substantial repertoire of conserved enzymes including those involved in chromatin remodeling and histone modifications. These enzymes have been described to play vital roles in epigenetic mechanisms for spatio-temporal regulation of gene expression that are crucial for parasite growth and differentiation. For instance, histone deacetylases (HDAC), histone acetyltransferases (HAT) and methyltransferases (HMT) play key roles in cell cycle progression, and particularly in the control of variable surface gene expression involved in immune evasion by the parasite. These enzymes are therefore considered as valid therapeutic targets. The center started testing this hypothesis and reported the development of novel HDAC inhibitors against P. falciparum. More recently, preliminary data with dual-targeting compounds that were designed by fusing DHFR inhibitor scaffold with HDAC inhibitors showed potent antiplasmodial activity against resistant P. falciparum strains. The synergy of inhibiting both targets was confirmed in a combination assay where the combination of two individual drugs showed potent inhibition of the parasite growth (Pf 3D7) at low concentration. 

Project details

Genetics and Genomics

Feb 2022 — Feb 2025

$433,154

France