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

Sesquiterpenes are a rich source of covalent inhibitors with long history in traditional medicine and include several important therapeutics tool compounds. Herein, we report the total synthesis 16 sesquiterpene lactones via build/couple/pair strategy, including goyasensolide. Using an alkyne-tagged cellular probe proteomics analysis, discovered that goyazensolide selectively targets oncoprotein importin-5 (IPO5) for engagement. We further demonstrate inhibits translocation RASAL-2, cargo IPO5, into nucleus perturbs binding between IPO5 two specific viral nuclear localization sequences.