Cell-based screening of extracts of natural sources to search for inhibitors of the ubiquitin-proteasome system and identification of proteasome inhibitors from the fungus Remotididymella sp.

Soichiro Nishimura; Yuki Hitora; Teppei Kawahara; Mika Tanabe; Eisuke Ogata; Hikaru Kato; Pattaravadee Srikoon; Takashi Watanabe; Sachiko Tsukamoto; 塚本 佐知子; ツカモト サチコ

タイトル	en Cell-based screening of extracts of natural sources to search for inhibitors of the ubiquitin-proteasome system and identification of proteasome inhibitors from the fungus Remotididymella sp.
作成者	en Soichiro, Nishimura en Yuki, Hitora en Teppei, Kawahara en Mika, Tanabe en Eisuke, Ogata en Hikaru, Kato en Pattaravadee, Srikoon en Takashi, Watanabe en Sachiko, Tsukamoto ja 塚本, 佐知子 ja-Kana ツカモト, サチコ
権利情報	en (C)2022 Elsevier Ltd. All rights reserved. en This manuscript version is made available under the CC-BY-NC-ND 4.0 License.http://creativecommons.org/licenses/by-nc-nd/4.0/.
主題	Other en The ubiquitin-proteasome system Other en Cell-based screening Other en Proteasome inhibitor Other en Remotididymella sp. Other en Leptosphaerodione
内容注記	Abstract en The ubiquitin-proteasome system (UPS) regulates selective protein degradation to maintain protein homeostasis. Small molecules that inhibit the UPS-dependent protein degradation are promising anti-tumor agents. We report a cell-based luminescent assay using HeLa cells expressing luciferase-fused oxygen-dependent destruction domain (ODD) of hypoxia-inducible factor 1 α (HIF-1 α). ODD is degraded by the UPS and this assay system can aid in the identification of natural products that inhibit either process of the UPS, including ubiquitination/deubiquitination and proteasomal degradation. This reporter assay can exclude the influences of coloring or fluorescent compounds in extracts, thereby leading to effective high-throughput processing. The screening of 15,025 extracts of natural sources identified the culture extract of the fungus Remotididymella sp. (18F02908). Bioassay-guided isolation yielded two new polyketides, mellains A (1) and B (2), together with leptosphaerodione (3) and its acetone adduct 4. Compound 1 was revealed to have an unprecedented benzo[g]isoquinoline-8,10-dione skeleton. Evaluation of the biological activities demonstrated that these polyketides inhibit the proteasomal proteolysis. This is the first report of the identification of proteasome inhibitors from natural sources using a cell-based reporter assay targeting UPS inhibitors.
出版者	en Elsevier
日付	Issued2022-03-01
言語	eng
資源タイプ	journal article
出版タイプ	AM
資源識別子	HDL http://hdl.handle.net/2298/0002000056 , URI https://kumadai.repo.nii.ac.jp/records/2000056
関連	isVersionOf DOI https://doi.org/10.1016/j.bmcl.2022.128566
収録誌情報	PISSN 0960-894X en Bioorganic & Medicinal Chemistry Letters 巻59 開始ページ128566
ファイル	https://kumadai.repo.nii.ac.jp/record/2000056/files/j_bmcl_2022_128566.pdf 628 KB (application/pdf) Available2024-03-02
コンテンツ更新日時	2023-11-24