Targeting Lysine Deacetylases (KDACs) in Parasites

Qi Wang, Bruce A. Rosa, Bakela Nare, Kerrie Powell, Sergio Valente, Dante Rotili, Antonello Mai, Garland R. Marshall, Makedonka Mitreva

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors) is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs) are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum), kinetoplastids (Trypanosoma brucei and Leishmania donovani), and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus). Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast) in order to determine potential parasite-versus-host selectivity). The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC inhibitors in targeting Plasmodium to develop new anti-malarial treatments, and also pioneers experiments with these KDAC inhibitors as potential new anthelminthics. The selectivity observed begins to address the challenges of targeting specific parasitic diseases while limiting host toxicity.

Original languageEnglish (US)
Article numbere0004026
JournalPLoS Neglected Tropical Diseases
Volume9
Issue number9
DOIs
StatePublished - Sep 24 2015
Externally publishedYes

Fingerprint

Lysine
Parasites
Parasitic Diseases
Pharmaceutical Preparations
Epigenomics
Brugia malayi
Dirofilaria immitis
Communicable Disease Control
Haemonchus
Leishmania donovani
Trypanosoma brucei brucei
Plasmodium
Falciparum Malaria
Antimalarials
Enzyme Inhibitors
Drug Resistance
Libraries
Proteins
Fibroblasts
Cell Line

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Wang, Q., Rosa, B. A., Nare, B., Powell, K., Valente, S., Rotili, D., ... Mitreva, M. (2015). Targeting Lysine Deacetylases (KDACs) in Parasites. PLoS Neglected Tropical Diseases, 9(9), [e0004026]. https://doi.org/10.1371/journal.pntd.0004026

Targeting Lysine Deacetylases (KDACs) in Parasites. / Wang, Qi; Rosa, Bruce A.; Nare, Bakela; Powell, Kerrie; Valente, Sergio; Rotili, Dante; Mai, Antonello; Marshall, Garland R.; Mitreva, Makedonka.

In: PLoS Neglected Tropical Diseases, Vol. 9, No. 9, e0004026, 24.09.2015.

Research output: Contribution to journalArticle

Wang, Q, Rosa, BA, Nare, B, Powell, K, Valente, S, Rotili, D, Mai, A, Marshall, GR & Mitreva, M 2015, 'Targeting Lysine Deacetylases (KDACs) in Parasites', PLoS Neglected Tropical Diseases, vol. 9, no. 9, e0004026. https://doi.org/10.1371/journal.pntd.0004026
Wang Q, Rosa BA, Nare B, Powell K, Valente S, Rotili D et al. Targeting Lysine Deacetylases (KDACs) in Parasites. PLoS Neglected Tropical Diseases. 2015 Sep 24;9(9). e0004026. https://doi.org/10.1371/journal.pntd.0004026
Wang, Qi ; Rosa, Bruce A. ; Nare, Bakela ; Powell, Kerrie ; Valente, Sergio ; Rotili, Dante ; Mai, Antonello ; Marshall, Garland R. ; Mitreva, Makedonka. / Targeting Lysine Deacetylases (KDACs) in Parasites. In: PLoS Neglected Tropical Diseases. 2015 ; Vol. 9, No. 9.
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