Published December 10, 2020
| Version v1
Journal article
Open
Identification of a covalent importin-5 inhibitor, goyazensolide from a collective synthesis of furanoheliangolides
Authors/Creators
- 1. Departement of Organic Chemistry, NCCR Chemical Biology, Faculty of Science, University of Geneva, 1205 Geneva, Switzerland
- 2. Departement of Molecular Biology, NCCR Chemical Biology, Faculty of Science, University of Geneva, 1205 Geneva, Switzerland
Description
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 natural products 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 localisation sequences.
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