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Updated: Feb 20, 2026

Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
Published on: February 28, 2025
Following the Lead from Nature with Covalent Inhibitors
Roman Lagoutte1, Nicolas Winssinger2
1Faculty of Science, Department of Organic Chemistry NCCR Chemical Biology University of Geneva 30 quai Ernest Ansermet, CH-1205 Geneva.
Abstract:
Covalent inhibitors are re-emerging as pharmacologically interesting entities with several candidates having received recent approval for therapeutic intervention. Nature has embraced this strategy and many natural products possess mildly electrophilic moieties able to covalently engage a target protein. This review surveys recent case studies for the identification of the target proteins of natural products. While sesquiterpene lactones represent a vast repertoire of covalent inhibitors, they can also be found in other classes of natural products, with sometimes unusual mechanisms to unmask the electrophilic moieties. These examples ought to be inspiring for the development of new biochemical probes and tomorrow's first-in-class drugs.
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