Targeting epigenetic mechanisms for drug development against Neglected Parasitic Diseases: the A-ParaDDisE project and beyond

Mon9  Apr11:15am(30 mins)
Where:
Stream 3 - Physics 0.15 Main
Keynote Speaker:
Dr Raymond Pierce

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.
Schedule

Hosted By
British Society for Parasitology (BSP)
We are science based charitable society.
Event Logo Find us on Facebook Follow us on Twitter

Get the App
Get this event information on your mobile by
going to the appstore or google play and search for 'eventflo'
www.myeventflo.com/2048
Login
Eventflo Home
copyright British Society for Parasitology (BSP), eventflo, Labhoo Ltd 2018