Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis.
Background Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed. Methodolo...
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ftdoajarticles:oai:doaj.org/article:b93fb5a4fb9845fd9f3a21bef1371d65 2023-05-15T15:16:18+02:00 Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. Fumika Mi-Ichi Takeshi Ishikawa Vo Kha Tam Sharmina Deloer Shinjiro Hamano Tsuyoshi Hamada Hiroki Yoshida 2019-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007633 https://doaj.org/article/b93fb5a4fb9845fd9f3a21bef1371d65 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0007633 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007633 https://doaj.org/article/b93fb5a4fb9845fd9f3a21bef1371d65 PLoS Neglected Tropical Diseases, Vol 13, Iss 8, p e0007633 (2019) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2019 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007633 2022-12-31T07:48:33Z Background Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed. Methodology/principal findings Here, to develop new drugs against amoebiasis, we focused on E. histolytica adenosine 5'-phosphosulfate kinase (EhAPSK), an essential enzyme in Entamoeba sulfolipid metabolism. Fatty alcohol disulfates and cholesteryl sulfate, sulfolipids synthesized in Entamoeba, play important roles in trophozoite proliferation and cyst formation. These processes are closely associated with clinical manifestation and severe pathogenesis of amoebiasis and with disease transmission, respectively. We validated a combination approach of in silico molecular docking analysis and an in vitro enzyme activity assay for large scale screening. Docking simulation ranked the binding free energy between a homology modeling structure of EhAPSK and 400 compounds. The 400 compounds were also screened by a 96-well plate-based in vitro APSK activity assay. Among fifteen compounds identified as EhAPSK inhibitors by the in vitro system, six were ranked by the in silico analysis as having high affinity toward EhAPSK. Furthermore, 2-(3-fluorophenoxy)-N-[4-(2-pyridyl)thiazol-2-yl]-acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide, and auranofin, which were identified as EhAPSK inhibitors by both in silico and in vitro analyses, halted not only Entamoeba trophozoite proliferation but also cyst formation. These three compounds also dose-dependently impaired the synthesis of sulfolipids in E. histolytica. Conclusions/significance Hence, the combined approach of in silico and in vitro-based EhAPSK analyses identified compounds that can be evaluated for their effects on Entamoeba. This can provide leads for the development of new anti-amoebic and amoebiasis transmission-blocking drugs. This strategy can also be ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 13 8 e0007633 |
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Open Polar |
collection |
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 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Fumika Mi-Ichi Takeshi Ishikawa Vo Kha Tam Sharmina Deloer Shinjiro Hamano Tsuyoshi Hamada Hiroki Yoshida Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed. Methodology/principal findings Here, to develop new drugs against amoebiasis, we focused on E. histolytica adenosine 5'-phosphosulfate kinase (EhAPSK), an essential enzyme in Entamoeba sulfolipid metabolism. Fatty alcohol disulfates and cholesteryl sulfate, sulfolipids synthesized in Entamoeba, play important roles in trophozoite proliferation and cyst formation. These processes are closely associated with clinical manifestation and severe pathogenesis of amoebiasis and with disease transmission, respectively. We validated a combination approach of in silico molecular docking analysis and an in vitro enzyme activity assay for large scale screening. Docking simulation ranked the binding free energy between a homology modeling structure of EhAPSK and 400 compounds. The 400 compounds were also screened by a 96-well plate-based in vitro APSK activity assay. Among fifteen compounds identified as EhAPSK inhibitors by the in vitro system, six were ranked by the in silico analysis as having high affinity toward EhAPSK. Furthermore, 2-(3-fluorophenoxy)-N-[4-(2-pyridyl)thiazol-2-yl]-acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide, and auranofin, which were identified as EhAPSK inhibitors by both in silico and in vitro analyses, halted not only Entamoeba trophozoite proliferation but also cyst formation. These three compounds also dose-dependently impaired the synthesis of sulfolipids in E. histolytica. Conclusions/significance Hence, the combined approach of in silico and in vitro-based EhAPSK analyses identified compounds that can be evaluated for their effects on Entamoeba. This can provide leads for the development of new anti-amoebic and amoebiasis transmission-blocking drugs. This strategy can also be ... |
format |
Article in Journal/Newspaper |
author |
Fumika Mi-Ichi Takeshi Ishikawa Vo Kha Tam Sharmina Deloer Shinjiro Hamano Tsuyoshi Hamada Hiroki Yoshida |
author_facet |
Fumika Mi-Ichi Takeshi Ishikawa Vo Kha Tam Sharmina Deloer Shinjiro Hamano Tsuyoshi Hamada Hiroki Yoshida |
author_sort |
Fumika Mi-Ichi |
title |
Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
title_short |
Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
title_full |
Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
title_fullStr |
Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
title_full_unstemmed |
Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
title_sort |
characterization of entamoeba histolytica adenosine 5'-phosphosulfate (aps) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2019 |
url |
https://doi.org/10.1371/journal.pntd.0007633 https://doaj.org/article/b93fb5a4fb9845fd9f3a21bef1371d65 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 13, Iss 8, p e0007633 (2019) |
op_relation |
https://doi.org/10.1371/journal.pntd.0007633 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007633 https://doaj.org/article/b93fb5a4fb9845fd9f3a21bef1371d65 |
op_doi |
https://doi.org/10.1371/journal.pntd.0007633 |
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PLOS Neglected Tropical Diseases |
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13 |
container_issue |
8 |
container_start_page |
e0007633 |
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