{"_buckets": {"deposit": "08483823-a3c5-428d-b6c2-02379c1220e7"}, "_deposit": {"id": "52313", "owners": [], "pid": {"revision_id": 0, "type": "depid", "value": "52313"}, "status": "published"}, "_oai": {"id": "oai:tsukuba.repo.nii.ac.jp:00052313"}, "item_5_biblio_info_6": {"attribute_name": "\u66f8\u8a8c\u60c5\u5831", "attribute_value_mlt": [{"bibliographicIssueDates": {"bibliographicIssueDate": "2019-05", "bibliographicIssueDateType": "Issued"}, "bibliographicIssueNumber": "10", "bibliographicPageStart": "2019", "bibliographicVolumeNumber": "24", "bibliographic_titles": [{"bibliographic_title": "Molecules"}]}]}, "item_5_description_4": {"attribute_name": "\u6284\u9332", "attribute_value_mlt": [{"subitem_description": "Covalent agonists of PPAR\u03b3 cause unique receptor conformational changes and behave as selective PPAR\u03b3 modulators, whereas there are few covalent agonists other than endogenous unsaturated fatty acids metabolites. Previously, we established a cell-based strategy to identify new PPAR\u03b3 ligands and synthesized a new-type of covalent agonist that possesses the hybrid structure of a plant-derived cinnamic acid derivative and GW9662, a covalent antagonist. Herein, we report six analogues that differ in how the two fragments are linked together. Compounds with a simplified linker showed potent agonistic activity with improved EC50 values (less than 5 nM), indicating that close proximity between the two fragments improves binding affinity. When the position of cinnamic acid moiety was placed at 4\u2032 carbon of aniline ring, PPAR\u03b3 agonist activity was completely abolished. Docking studies suggested that the activation profile likely depends on interaction with the cavity around helix 3, \u03b2-sheet, and \u03a9-loop region in the ligand-binding domain. Furthermore, a cell-based assay revealed that agonist-type compounds activate PPAR\u03b3 transcription in a manner dependent on covalent linkage with the Cys285 residue leading to prolonged transactivation. This activation feature reflects pharmacological benefits of covalent drugs, suggesting that these hybrid compounds may serve as potential leads for a new-class of covalent PPAR\u03b3 ligands.", "subitem_description_type": "Abstract"}]}, "item_5_publisher_27": {"attribute_name": "\u51fa\u7248\u8005", "attribute_value_mlt": [{"subitem_publisher": "MDPI"}]}, "item_5_relation_10": {"attribute_name": "PubMed\u756a\u53f7", "attribute_value_mlt": [{"subitem_relation_type_id": {"subitem_relation_type_id_text": "31137814", "subitem_relation_type_select": "PMID"}}]}, "item_5_relation_11": {"attribute_name": "DOI", "attribute_value_mlt": [{"subitem_relation_type_id": {"subitem_relation_type_id_text": "10.3390/molecules24102019", "subitem_relation_type_select": "DOI"}}]}, "item_5_rights_12": {"attribute_name": "\u6a29\u5229", "attribute_value_mlt": [{"subitem_rights": "\u00a9 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)."}]}, "item_5_select_15": {"attribute_name": "\u8457\u8005\u7248\u30d5\u30e9\u30b0", "attribute_value_mlt": [{"subitem_select_item": "publisher"}]}, "item_5_source_id_7": {"attribute_name": "ISSN", "attribute_value_mlt": [{"subitem_source_identifier": "1420-3049", "subitem_source_identifier_type": "ISSN"}]}, "item_creator": {"attribute_name": "\u8457\u8005", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "\u7912\u7530, \u535a\u5b50"}, {"creatorName": "\u30a4\u30bd\u30c0, \u30d2\u30ed\u30b3", "creatorNameLang": "ja-Kana"}, {"creatorName": "ISODA, Hiroko", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "113", "nameIdentifierScheme": "WEKO"}, {"nameIdentifier": "00375429", "nameIdentifierScheme": "e-Rad", "nameIdentifierURI": "https://nrid.nii.ac.jp/ja/nrid/1000000375429"}, {"nameIdentifier": "0000001303", "nameIdentifierScheme": "\u7b51\u6ce2\u5927\u5b66\u7814\u7a76\u8005\u7dcf\u89a7", "nameIdentifierURI": "http://trios.tsukuba.ac.jp/researcher/0000001303"}]}, {"creatorNames": [{"creatorName": "\u5bae\u524d, \u53cb\u7b56"}, {"creatorName": "\u30df\u30e4\u30de\u30a8, \u30e6\u30a6\u30b5\u30af", "creatorNameLang": "ja-Kana"}, {"creatorName": "MIYAMAE, Yusaku", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "204918", "nameIdentifierScheme": "WEKO"}, {"nameIdentifier": "30610240", "nameIdentifierScheme": "e-Rad", "nameIdentifierURI": "https://nrid.nii.ac.jp/ja/nrid/1000030610240"}, {"nameIdentifier": "0000003934", "nameIdentifierScheme": "\u7b51\u6ce2\u5927\u5b66\u7814\u7a76\u8005\u7dcf\u89a7", "nameIdentifierURI": "http://trios.tsukuba.ac.jp/researcher/0000003934"}]}, {"creatorNames": [{"creatorName": "Utsugi, Yuki", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "214764", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Kobuchi, Hirona", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "214765", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Kawamura, Yukio", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "214766", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Atito, Ahmed Salahelden Aboelhamd", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "214767", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Nagao, Masaya", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "214768", "nameIdentifierScheme": "WEKO"}]}]}, "item_files": {"attribute_name": "\u30d5\u30a1\u30a4\u30eb\u60c5\u5831", "attribute_type": "file", "attribute_value_mlt": [{"accessrole": "open_date", "date": [{"dateType": "Available", "dateValue": "2019-09-27"}], "displaytype": "detail", "download_preview_message": "", "file_order": 0, "filename": "molecules24-10.pdf", "filesize": [{"value": "1.3 MB"}], "format": "application/pdf", "future_date_message": "", "is_thumbnail": false, "licensetype": "license_6", "mimetype": "application/pdf", "size": 1300000.0, "url": {"label": "molecules24-10", "url": "https://tsukuba.repo.nii.ac.jp/record/52313/files/molecules24-10.pdf"}, "version_id": "8ced9558-3798-4cb5-8ef7-2af295f01998"}]}, "item_language": {"attribute_name": "\u8a00\u8a9e", "attribute_value_mlt": [{"subitem_language": "eng"}]}, "item_resource_type": {"attribute_name": "\u8cc7\u6e90\u30bf\u30a4\u30d7", "attribute_value_mlt": [{"resourcetype": "journal article", "resourceuri": "http://purl.org/coar/resource_type/c_6501"}]}, "item_title": "Importance of the Proximity and Orientation of Ligand-Linkage to the Design of Cinnamate-GW9662 Hybrid Compounds as Covalent PPAR\u03b3 Agonists", "item_titles": {"attribute_name": "\u30bf\u30a4\u30c8\u30eb", "attribute_value_mlt": [{"subitem_title": "Importance of the Proximity and Orientation of Ligand-Linkage to the Design of Cinnamate-GW9662 Hybrid Compounds as Covalent PPAR\u03b3 Agonists"}]}, "item_type_id": "5", "owner": "1", "path": ["160/523", "160/7662", "3/62/5595/6031"], "permalink_uri": "http://hdl.handle.net/2241/00157737", "pubdate": {"attribute_name": "\u516c\u958b\u65e5", "attribute_value": "2019-09-27"}, "publish_date": "2019-09-27", "publish_status": "0", "recid": "52313", "relation": {}, "relation_version_is_last": true, "title": ["Importance of the Proximity and Orientation of Ligand-Linkage to the Design of Cinnamate-GW9662 Hybrid Compounds as Covalent PPAR\u03b3 Agonists"], "weko_shared_id": 5}