{"created":"2024-10-07T07:26:40.556480+00:00","id":2000345,"links":{},"metadata":{"_buckets":{"deposit":"abb3ec01-a5b8-4fe2-9937-a87a191ae89f"},"_deposit":{"created_by":52,"id":"2000345","owner":"52","owners":[52],"pid":{"revision_id":0,"type":"depid","value":"2000345"},"status":"published"},"_oai":{"id":"oai:tokushima-u.repo.nii.ac.jp:02000345","sets":["1713853213384:1713853295607"]},"author_link":["225"],"control_number":"2000345","item_10001_biblio_info_7":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2010-04-13","bibliographicIssueDateType":"Issued"},"bibliographicIssueNumber":"4","bibliographicPageStart":"e659","bibliographicVolumeNumber":"4","bibliographic_titles":[{"bibliographic_title":"PLoS Neglected Tropical Diseases","bibliographic_titleLang":"en"}]}]},"item_10001_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Background: The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the γ-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay.\nMethodology/Principal Findings: Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were ∼20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03≤EC50<3 µM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics.\nConclusions/Significance: The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome.","subitem_description_language":"en","subitem_description_type":"Abstract"}]},"item_10001_publisher_8":{"attribute_name":"出版者","attribute_value_mlt":[{"subitem_publisher":"PLOS","subitem_publisher_language":"en"}]},"item_10001_rights_15":{"attribute_name":"権利情報","attribute_value_mlt":[{"subitem_rights":"© 2010 Sharlow et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.","subitem_rights_language":"en"}]},"item_10001_source_id_9":{"attribute_name":"収録物ID","attribute_value_mlt":[{"subitem_source_identifier":"19352735","subitem_source_identifier_type":"EISSN"},{"subitem_source_identifier":"19352727","subitem_source_identifier_type":"PISSN"}]},"item_10001_version_type_20":{"attribute_name":"出版タイプ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_970fb48d4fbd8a85","subitem_version_type":"VoR"}]},"item_1715043197608":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"open access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_abf2"}]},"item_1722929371688":{"attribute_name":"出版社版DOI","attribute_value_mlt":[{"subitem_relation_name":[{"subitem_relation_name_language":"ja","subitem_relation_name_text":"10.1371/journal.pntd.0000659"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://doi.org/10.1371/journal.pntd.0000659","subitem_relation_type_select":"DOI"}}]},"item_1723180141928":{"attribute_name":"EID","attribute_value_mlt":[{"subitem_identifier_type":"URI","subitem_identifier_uri":"235907"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Sharlow, Elizabeth R.","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Lyda, Todd A.","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Dodson, Heidi C.","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Mustata, Gabriela","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Morris, Meredith T.","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Leimgruber, Stephanie S.","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Lee, Kuo-Hsiung","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"柏田, 良樹","creatorNameLang":"ja"},{"creatorName":"カシワダ, ヨシキ","creatorNameLang":"ja-Kana"},{"creatorName":"Kashiwada, Yoshiki","creatorNameLang":"en"}],"familyNames":[{"familyName":"柏田","familyNameLang":"ja"},{"familyName":"カシワダ","familyNameLang":"ja-Kana"},{"familyName":"Kashiwada","familyNameLang":"en"}],"givenNames":[{"givenName":"良樹","givenNameLang":"ja"},{"givenName":"ヨシキ","givenNameLang":"ja-Kana"},{"givenName":"Yoshiki","givenNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"225","nameIdentifierScheme":"WEKO"},{"nameIdentifier":"140820/profile-ja.html","nameIdentifierScheme":"徳島大学 教育研究者総覧","nameIdentifierURI":"http://pub2.db.tokushima-u.ac.jp/ERD/person/140820/profile-ja.html"},{"nameIdentifier":"30169429","nameIdentifierScheme":"e-Rad_Researcher","nameIdentifierURI":"https://nrid.nii.ac.jp/ja/search/?qm=30169429"}]},{"creatorNames":[{"creatorName":"Close, David","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Lazo, John S.","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Morris, James C.","creatorNameLang":"en"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_access","date":[{"dateType":"Available","dateValue":"2024-01-01"}],"displaytype":"detail","filename":"pntd_4_4_e659.pdf","filesize":[{"value":"285 KB"}],"format":"application/pdf","licensetype":"license_0","mimetype":"application/pdf","url":{"objectType":"fulltext","url":"https://tokushima-u.repo.nii.ac.jp/record/2000345/files/pntd_4_4_e659.pdf"},"version_id":"71b94304-447b-44f8-9dc7-5942f29103b7"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"journal article","resourceuri":"http://purl.org/coar/resource_type/c_6501"}]},"item_title":"A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity","subitem_title_language":"en"}]},"item_type_id":"40001","owner":"52","path":["1713853295607"],"pubdate":{"attribute_name":"PubDate","attribute_value":"2024-01-01"},"publish_date":"2024-01-01","publish_status":"0","recid":"2000345","relation_version_is_last":true,"title":["A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity"],"weko_creator_id":"52","weko_shared_id":-1},"updated":"2025-03-19T05:28:39.402390+00:00"}