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).
The disease burden imposed by parasitic infections worldwide is tremendous, and disproportionately affects poor countries in tropical and subtropical regions. Nowadays, malaria and schistosomiasis remain two of the most challenging parasitic infections. Indeed, these two diseases collectively infect about half billion people, mainly in developing countries, cause hundreds of thousands of deaths annually, and represent a major economic burden worldwide. With no effective vaccines currently available, the drug treatments remain the only option for their control. Anyway, the therapies for these diseases face problems due to developing resistance, severe side-effects, prolonged dosing schedules, and low efficacy at all disease stages, thus the development of new drugs is considered a global priority.
Parasites are eukaryotic organisms and, as such, share common epigenetic mechanisms, histone and DNA marks, and epigenetic enzymes with humans. The epigenetic mechanisms play important roles in parasitic development, and histone and DNA modifying enzymes have shown to play 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. Recent studies have shown the role played by histone and DNA modifying enzymes in the capacity of parasites to quickly adapt to a different host environment, to evade host immune responses or alter their phenotypes at several key points of their life cycles. Therefore, targeting the parasite epigenome and, to some extent, also the host human epigenome has been proposed as a new strategy for the treatment and control of parasitic infections.
In the present proposal we hope to capitalize our experience about the development of epigenetic modulators as anticancer and potential antiparasitic agents, offering a hit expansion and optimization process for various already identified hit/lead compounds targeting three different parasitic epi-targets (HDACs, SIRTs, and DNMTs), pursuing the final goal to select optimized candidates to be advanced to tests in preclinical models of malaria and schistosomiasis.