Authors

R Pierce¹;  ¹ CIIL, CNRS UMR 8204, France

Discussion

Introduction: The "writers", "erasers" or "readers" of epigenetic marks on chromatin are attractive targets for drug development in numerous pathologies, including neglected parasitic diseases. Parasite-selective inhibitors may be designed to exploit key differences in parasite enzymes compared to human orthologues. Moreover, species-specific sensitivities to the blocking of a particular enzyme activity can be exploited. These strategies were pursued during the A-ParaDDisE project, funded by the EC, involving research teams in Europe, Brazil and Australia, targeting schistosomiasis, leishmaniasis, Chagas disease and malaria.

Methods: Target validation by gene or transcript knockdown and phenotypic screening with inhibitors allowed prioritization of enzymes for target-based screening. Production of active, recombinant proteins, structural studies and assay development permitted both high-throughput and in silico compound screening. Hits prioritized on the basis of potency of enzyme inhibition and selectivity for the parasite followed bio-guided optimization steps to generate lead compounds for ADME studies and pre-clinical in vivo testing.

Results: Both phenotypic and target-based screening strategies generated a large number of hits. Leads were selected on the basis of their low toxicity, bio-availability and in vivo efficacy. The structure-based optimization of inhibitors of the validated therapeutic target Schistosoma mansoni histone deacetylase 8 (SmHDAC8) proved the concept that parasite selectivity can be achieved. Investigation of the interactome of SmHDAC8 indicates key roles in cytoskeletal integrity and cell division.

Conclusion: Enzymes involved in epigenetic processes are valid therapeutic targets for parasitic diseases and selective inhibitors are currently under development as drug leads.