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Epigenetics at the service of neglected diseases


Schematic representation of the interaction between the anti-cancer drug SAHA (orange) and the epigenetic enzyme HDAC 8 from human (blue) or schistosomes (green). The differences observed between these two modes of binding helped to unveil candidate drugs targeting specifically HDAC 8 in schistosomes. By binding to HDAC 8, the J1075 molecule (pink) causes the death of larval schistosomes and the mismatching of pairs of worms, which normally remain paired throughout their lives in their host and can produce tens of thousands of eggs responsible for the effects of schistosomiasis. © Christophe Romier, Raymond Pierce

Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni.

Marek M, Kannan S, Hauser AT, Moraes Mourão M, Caby S, Cura V, Stolfa DA, Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M, Cavarelli J, Pierce RJ, Romier C.

PLoS Pathog Sep 2013

Sept. 26, 2013

The identification of new drug candidates potentially effective against schistosomiasis has brought to light the interest to target the epigenome of pathogens in order to treat neglected diseases that affect millions of people worldwide. This work was published in PLoS Pathogens by researchers from the IGBMC in Strasbourg (CNRS / Inserm / Université de Strasbourg) and the Centre for Infection and Immunity of Lille (CNRS / Inserm / Institut Pasteur Lille / Université Lille 2), in collaboration with the Albert-Ludwig University of Freiburg-im-Breisgau, Germany, the Martin-Luther University of Halle-Wittenberg, Germany, and the Research Center René Rachou of Belo Horizonte in Brazil.


Many tropical infections, particularly endemic in poor populations of Africa, Asia and South America, are called "neglected", since the pharmaceutical industry is paying them little attention because of the low profitability of the marketing of new treatments. Though, these diseases, the best known of which is certainly malaria, are responsible for hundreds of thousands of deaths each year and have a significantly negative impact on the global economy as they reduce the productivity of adults in the labor force and keep the infected people in a state of poverty and disease.


Malaria is receiving more and more attention from both health authorities and researchers who now focus on developing therapeutic strategies adapted to infected populations. But this is not the case for other neglected diseases, for which there is no effective long-term treatment, which could avoid the emergence of new resistant strains. This is notably the case of schistosomiasis, a disease caused by parasitic worms of the genus Schistosoma, which is responsible for the deaths of more than 300,000 people per year. There are 200 million people infected with schistosomiasis in the world and 800 million subject at risk of infection.


Under the project SEtTReND (Schistosoma Epigenetics - Targets, Regulation, New Drugs) involving European and Brazilian laboratories, the researchers discovered, through a multidisciplinary approach, candidates drugs targeting specifically histone deacetylase 8 (HDAC 8) of Schistosoma mansoni. This HDAC is part of the epigenetic enzymes that allow cells to adapt to their environment. According to the researchers, these drug candidates could also be active against others pathogenic worms, such as tapeworms or those that cause liver fluke.


Building on the project SetTReND, which ended in 2012, the new program A-ParaDDisE (Anti-Parasitic Drug Discovery in Epigenetics) will bring together starting 2014 a large number of European, Brazilian and Australian laboratories in order to uncover molecules of interest for interfering with the epigenetic mechanisms that drive the parasites of schistosomiasis, but also other neglected diseases such as malaria, trypanosomiasis and leishmaniasis.

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