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. We 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. In the present project, we will exploit the basic principles and major results to target P. falciparum and develop the inhibitors into potent, selective and in vivo active drug candidates. This will lead to the generation of novel hybrid antiparasitic compounds with a high potential to delay or circumvent the development of resistance and the ability to provide additional range of treatments with effective combination options. In parallel, we propose to define the mode of action of the most promising dual-targeting compounds that will give rise to new approaches for examining and manipulating biological processes and will enhance the understanding of how PfHDAC enzymes work. This could be achieved through the chemistry/biology cross fertilization and the generated knowledge will likely continue to improve the quality of treatments against apicomplexans.
Keywords: Plasmodium falciparum, histone deacetylase, dihydrofolate reductase, drug design, dual-targeting inhibitors.