Targeting Lysine Deacetylases (KDACs) in Parasites.
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 know...
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ftdoajarticles:oai:doaj.org/article:a3ae8a6ca3e445bc8db3fa8fdcbf448b 2023-05-15T15:16:22+02:00 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 2015-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004026 https://doaj.org/article/a3ae8a6ca3e445bc8db3fa8fdcbf448b EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4581690?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004026 https://doaj.org/article/a3ae8a6ca3e445bc8db3fa8fdcbf448b PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004026 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004026 2022-12-31T06:31:52Z 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 ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 9 e0004026 |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Qi Wang Bruce A Rosa Bakela Nare Kerrie Powell Sergio Valente Dante Rotili Antonello Mai Garland R Marshall Makedonka Mitreva Targeting Lysine Deacetylases (KDACs) in Parasites. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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 ... |
format |
Article in Journal/Newspaper |
author |
Qi Wang Bruce A Rosa Bakela Nare Kerrie Powell Sergio Valente Dante Rotili Antonello Mai Garland R Marshall Makedonka Mitreva |
author_facet |
Qi Wang Bruce A Rosa Bakela Nare Kerrie Powell Sergio Valente Dante Rotili Antonello Mai Garland R Marshall Makedonka Mitreva |
author_sort |
Qi Wang |
title |
Targeting Lysine Deacetylases (KDACs) in Parasites. |
title_short |
Targeting Lysine Deacetylases (KDACs) in Parasites. |
title_full |
Targeting Lysine Deacetylases (KDACs) in Parasites. |
title_fullStr |
Targeting Lysine Deacetylases (KDACs) in Parasites. |
title_full_unstemmed |
Targeting Lysine Deacetylases (KDACs) in Parasites. |
title_sort |
targeting lysine deacetylases (kdacs) in parasites. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0004026 https://doaj.org/article/a3ae8a6ca3e445bc8db3fa8fdcbf448b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004026 (2015) |
op_relation |
http://europepmc.org/articles/PMC4581690?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004026 https://doaj.org/article/a3ae8a6ca3e445bc8db3fa8fdcbf448b |
op_doi |
https://doi.org/10.1371/journal.pntd.0004026 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
9 |
container_start_page |
e0004026 |
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1766346653701242880 |