Malaria parasites have a complex life cycle involving functionally distinct forms in two different host species. This requires rapid transition between morphological states and tightly regulated gene expression. Posttranslational modification (PTM) enzymes involved in regulating gene expression and stage-specific conversion are therefore promising targets for the development of novel antimalarial inhibitors. Approaches targeting proteins involved in PTMs have been successfully used to control other human diseases. Two drugs that target histone deacetylase (HDAC) enzymes are now clinically approved for treatment of cancer. Several HDAC inhibitors have also been shown to have promising antimalarial profiles.
We have shown that hydroxamate-based HDAC inhibitors can have potent in vitro activity against asexual blood stages of the two major human malaria parasite species, Plasmodium falciparum and P. vivax (IC50 ~20-300nM). In this stage of the parasites lifecycle, the compounds have been shown to act by causing histone protein hyperacetylation and de-regulation of normal parasite transcriptional control. Our studies on the effect of HDAC inhibitors on other life cycle stages have also shown that the development of exo-erythrocytic stage P. berghei sporozoites infecting human liver cells is potently inhibited by these compounds (IC50 ~150nM). Here, we present new data to show that these HDAC inhibitors have activity against the gametocyte stage of the parasite, making HDACs potential new targets for development of transmission blocking drugs. Furthermore, preliminary studies show that one clinically approved anti-cancer HDAC inhibitor, SAHA, protects mice from severe symptoms in an experimental cerebral malaria (ECM) mouse model. This effect is associated with host serum cytokine changes, notably an increase in IL-10 levels. Studies are now underway to confirm these findings in an ECM rescue model. Results of this work may lead to development of a new approach for adjunctive treatment of cerebral malaria.