Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides

[Image: see text] Sesquiterpenes are a rich source of covalent inhibitors with a long history in traditional medicine and include several important therapeutics and tool compounds. Herein, we report the total synthesis of 16 sesquiterpene lactones via a build/couple/pair strategy, including goyasens...

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Autores principales: Liu, Weilong, Patouret, Rémi, Barluenga, Sofia, Plank, Michael, Loewith, Robbie, Winssinger, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227592/
https://www.ncbi.nlm.nih.gov/pubmed/34235256
http://dx.doi.org/10.1021/acscentsci.1c00056
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author Liu, Weilong
Patouret, Rémi
Barluenga, Sofia
Plank, Michael
Loewith, Robbie
Winssinger, Nicolas
author_facet Liu, Weilong
Patouret, Rémi
Barluenga, Sofia
Plank, Michael
Loewith, Robbie
Winssinger, Nicolas
author_sort Liu, Weilong
collection PubMed
description [Image: see text] Sesquiterpenes are a rich source of covalent inhibitors with a long history in traditional medicine and include several important therapeutics and tool compounds. Herein, we report the total synthesis of 16 sesquiterpene lactones via a build/couple/pair strategy, including goyasensolide. Using an alkyne-tagged cellular probe and proteomics analysis, we discovered that goyazensolide selectively targets the oncoprotein importin-5 (IPO5) for covalent engagement. We further demonstrate that goyazensolide inhibits the translocation of RASAL-2, a cargo of IPO5, into the nucleus and perturbs the binding between IPO5 and two specific viral nuclear localization sequences.
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spelling pubmed-82275922021-07-06 Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides Liu, Weilong Patouret, Rémi Barluenga, Sofia Plank, Michael Loewith, Robbie Winssinger, Nicolas ACS Cent Sci [Image: see text] Sesquiterpenes are a rich source of covalent inhibitors with a long history in traditional medicine and include several important therapeutics and tool compounds. Herein, we report the total synthesis of 16 sesquiterpene lactones via a build/couple/pair strategy, including goyasensolide. Using an alkyne-tagged cellular probe and proteomics analysis, we discovered that goyazensolide selectively targets the oncoprotein importin-5 (IPO5) for covalent engagement. We further demonstrate that goyazensolide inhibits the translocation of RASAL-2, a cargo of IPO5, into the nucleus and perturbs the binding between IPO5 and two specific viral nuclear localization sequences. American Chemical Society 2021-05-25 2021-06-23 /pmc/articles/PMC8227592/ /pubmed/34235256 http://dx.doi.org/10.1021/acscentsci.1c00056 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Liu, Weilong
Patouret, Rémi
Barluenga, Sofia
Plank, Michael
Loewith, Robbie
Winssinger, Nicolas
Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides
title Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides
title_full Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides
title_fullStr Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides
title_full_unstemmed Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides
title_short Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides
title_sort identification of a covalent importin-5 inhibitor, goyazensolide, from a collective synthesis of furanoheliangolides
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227592/
https://www.ncbi.nlm.nih.gov/pubmed/34235256
http://dx.doi.org/10.1021/acscentsci.1c00056
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