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Title
  • 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.
Creator
    • 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
Rights
  • 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/.
Subject
  • Other en The ubiquitin-proteasome system
  • Other en Cell-based screening
  • Other en Proteasome inhibitor
  • Other en Remotididymella sp.
  • Other en Leptosphaerodione
Description
  • 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.
Publisher en Elsevier
Date
    Issued2022-03-01
Language
  • eng
Resource Type journal article
Version Type AM
Identifier HDL http://hdl.handle.net/2298/0002000056 , URI https://kumadai.repo.nii.ac.jp/records/2000056
Relation
  • isVersionOf DOI https://doi.org/10.1016/j.bmcl.2022.128566
Journal
    • PISSN 0960-894X
      • en Bioorganic & Medicinal Chemistry Letters
      • Volume Number59 Page Start128566
File
Oaidate 2023-11-24