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Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone d...

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Autores principales: Chua, Ming Jang, Tng, Jiahui, Hesping, Eva, Fisher, Gillian M., Goodman, Christopher D., Skinner-Adams, Tina, Do, Darren, Lucke, Andrew J., Reid, Robert C., Fairlie, David P., Andrews, Katherine T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463797/
https://www.ncbi.nlm.nih.gov/pubmed/34560571
http://dx.doi.org/10.1016/j.ijpddr.2021.08.006
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author Chua, Ming Jang
Tng, Jiahui
Hesping, Eva
Fisher, Gillian M.
Goodman, Christopher D.
Skinner-Adams, Tina
Do, Darren
Lucke, Andrew J.
Reid, Robert C.
Fairlie, David P.
Andrews, Katherine T.
author_facet Chua, Ming Jang
Tng, Jiahui
Hesping, Eva
Fisher, Gillian M.
Goodman, Christopher D.
Skinner-Adams, Tina
Do, Darren
Lucke, Andrew J.
Reid, Robert C.
Fairlie, David P.
Andrews, Katherine T.
author_sort Chua, Ming Jang
collection PubMed
description Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC(50) 5–50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56–118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC(50) 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC(50) 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria.
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spelling pubmed-84637972021-10-01 Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice Chua, Ming Jang Tng, Jiahui Hesping, Eva Fisher, Gillian M. Goodman, Christopher D. Skinner-Adams, Tina Do, Darren Lucke, Andrew J. Reid, Robert C. Fairlie, David P. Andrews, Katherine T. Int J Parasitol Drugs Drug Resist Regular article Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC(50) 5–50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56–118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC(50) 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC(50) 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria. Elsevier 2021-08-23 /pmc/articles/PMC8463797/ /pubmed/34560571 http://dx.doi.org/10.1016/j.ijpddr.2021.08.006 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular article
Chua, Ming Jang
Tng, Jiahui
Hesping, Eva
Fisher, Gillian M.
Goodman, Christopher D.
Skinner-Adams, Tina
Do, Darren
Lucke, Andrew J.
Reid, Robert C.
Fairlie, David P.
Andrews, Katherine T.
Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice
title Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice
title_full Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice
title_fullStr Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice
title_full_unstemmed Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice
title_short Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice
title_sort histone deacetylase inhibitor ar-42 and achiral analogues kill malaria parasites in vitro and in mice
topic Regular article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463797/
https://www.ncbi.nlm.nih.gov/pubmed/34560571
http://dx.doi.org/10.1016/j.ijpddr.2021.08.006
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