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Martin Marek1, Tajith B Shaik1, Manfred Jung2

  • 1Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, 67404 Illkirch Cedex, France.

Biologie Aujourd'Hui
|March 23, 2017
PubMed
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Targeting pathogen epigenetic enzymes, like Schistosoma mansoni histone deacetylase 8 (smHDAC8), offers a novel strategy for developing anti-neglected disease epidrugs. This approach also informs potential treatments for human diseases, including cancer.

Area of Science:

  • Biochemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Epigenetic mechanisms regulate nuclear processes; their deregulation is linked to human diseases.
  • Epigenetic drugs (epidrugs) leverage the reversibility of epigenetic modifications.
  • Targeting pathogen-specific epigenetic enzymes presents a novel therapeutic strategy.

Purpose of the Study:

  • To develop drug leads targeting pathogen epigenetic enzymes for neglected diseases.
  • To investigate the structural specificities of Schistosoma mansoni histone deacetylase 8 (smHDAC8) compared to human homologs.
  • To design selective inhibitors for smHDAC8 using a structure-based approach.

Main Methods:

  • Structure-based drug design targeting smHDAC8.
  • Comparative structural analysis of smHDAC8 and human HDAC8.

Related Experiment Videos

  • Development of pathogen-specific inhibitors utilizing enzyme structural specificities.

    • Main Results:

    • Designed drug leads with higher selectivity for smHDAC8 over human HDAC8.
    • Identified pathogen-specific structural features in smHDAC8 for inhibitor design.
    • Demonstrated the potential of targeting smHDAC8 for anti-parasitic drug development.

    Conclusions:

    • Epigenetic enzymes from pathogens are viable targets for developing anti-pathogenic epidrugs against neglected diseases.
    • The developed structure-based approach provides a proof of concept for targeting smHDAC8.
    • Findings can inform the development of epidrugs for both neglected and human diseases, including cancer.