Modulators of epigenetic targets for the treatment of parasitic diseases.
The aim of the present project is to feed the drug development pipeline for malaria and schistosomiasis by targeting the enzymes responsible for the epigenetic processes that take place in the causing parasites. The disease burden imposed by these parasitic infections worldwide is huge, and disproportionately affects poor countries in tropical and subtropical regions. There are no effective vaccines currently available, and the drug treatments remain in the front line of diseases' control. The development of new drug treatments must aim at combating developing resistance and replacing other unsatisfactory approaches due to significant side-effects, prolonged treatment regimens and/or low efficacy at all disease stages. Parasites are eukaryotic organisms and, as such, share common epigenetic mechanisms, histone and DNA marks, and epigenetic enzymes with humans. Histone and DNA modifying enzymes have vital roles in the growth and survival of parasites. Moreover, parasitic-infected cells can be considered like cancer cells in terms of intensive metabolic activity and invisibility to host immune system. Therefore, targeting the parasite epigenome and, to some extent, also the human host epigenome has been proposed as a new strategy for the treatment of parasitic diseases. In the present proposal we aim to capitalize the experience made in the last years about the development of epigenetic modulators as potential antiparasitic agents, offering a hit expansion and optimization process for various already identified hit/lead compounds targeting three different parasitic epi-targets: histone deacetylases (HDACs), sirtuins (SIRTs), and DNA methyltransferases (DNMT).