New drugs for parasitic neglected tropical diseases
The A-PARADDISE project has provided data for the drug development pipeline for NTDs, in particular leishmaniasis, Chagas disease, malaria and schistosomiasis. These diseases infect millions of people globally and represent a major economic burden fuelled by associated poverty. Targeting epigenetic mechanisms, the A-PARADDISE team identified all the histone modifying enzymes (HMEs) in the parasites. Significant differences, particularly in the catalytic pocket, compared to their human counterparts are likely to allow the development of selective inhibitors that are drug candidates. Transcriptome studies helped identify gene expression signatures in parasites after selective HME inhibition. Gene knockout studies in the Chagas disease parasite, Trypanosoma cruzi (T. cruzi), revealed two histone deacetylases (HDACs) and a methyltransferase essential for parasite growth and survival. After extensive protein engineering, two T. cruzi HMEs have been produced as active enzymes. One of these has been submitted to the European Lead Factory (ELF) for high throughput screening. In addition, a Schistosoma mansoni (S. mansoni) methyltransferase has also been produced as an active enzyme and crystallized. For the essential S. mansoni HDAC8, bioguided inhibitor optimisation was carried out and this yielded compounds with increased selectivity and potency against the parasite in vitro. Out of more than 500 compounds screened using HME inhibitors, more than 100 hits were identified. Pharmacokinetic and toxicity studies were carried out on the most promising hits and in vivo testing was done in mouse models for Plasmodium, T. cruzi and S. mansoni infections. Three compounds with significant in vivo activity have so far been identified and testing is ongoing for several other compounds. Research activities of the A-PARADDISE project have validated the strategy whereby targeting parasite epigenetic processes may be very fruitful for drug development. Compounds already identified and screening of the T. cruzi HDAC through ELF may lead to collaborative projects with pharmaceutical industry partners.
Keywords
NTDs, A-PARADDISE, epigenetic, HME, T. cruzi, S. mansoni
