Plasmodium falciparum histone deacetylases: enzymes involved in gene regulation as new antimalarial drug targets

Abstract

Parasite resistance to current antimalarials is driving the search for new agents that act on novel parasite targets. One drug discovery strategy is to identify molecular targets in Plasmodium that are already being pursued for other diseases. Using this 'piggy-back' approach we are investigating a class of poorly studied P. falciparum enzymes, histone deacetylases (HDACs), which have been the target of anti-tumour drug development for decades. While some natural product HDAC inhibitors (eg apicidin and TSA) kill Plasmodium species in vitro, they also kill human cells at comparable concentrations, compromising their potential as drug candidates. We have since shown that a range of HDAC inhibitors are active against P. falciparum at 占concentrations and in vivo in a rodent malaria model. These HDAC inhibitors are more bioavailable than TSA and apicidin and support the idea that PfHDACs may be useful antimalarial targets. We have now engineered new compounds that are an order of magnitude more cytotoxic in vitro to P. falciparum (IC50, 3-334 nM) and display significantly less anti-proliferative activity against healthy host cells. Treatment of P. falciparum infected erythrocytes with these compounds causes stage-specific growth inhibition, results in hyperacetylation of parasite histones, and alters the RNA expression profile of several P. falciparum genes. These compounds are potential leads for the development of a new class of antimalarials with a different mechanism of action against the parasite than existing agents and may be useful tools in the study of P. falciparum gene regulation.