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

Weilong Liu; Rémi Patouret; Sofia Barluenga; Michael Plank; Robbie Loewith; Nicolas Winssinger

doi:10.1021/acscentsci.1c00056

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

ACS Cent Sci. 2021 Jun 23;7(6):954-962. doi: 10.1021/acscentsci.1c00056. Epub 2021 May 25.

Authors

Weilong Liu¹, Rémi Patouret¹, Sofia Barluenga¹, Michael Plank², Robbie Loewith², Nicolas Winssinger¹

Affiliations

¹ Department of Organic Chemistry, NCCR Chemical Biology, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, 1211 Geneva, Switzerland.
² Department of Molecular Biology, NCCR Chemical Biology, Faculty of Science, University of Geneva, 1205 Geneva, Switzerland.

Abstract

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.