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Title

Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments

AuthorsBecker, Daniel; Kaczmarska, Zuzanna ; Arkona, Christoph; Schulz, Robert; Tauber, Carolin; Wolber, Gerhard; Hilgenfeld, Rolf; Coll, Miquel ; Rademann, Jörg
Issue Date28-Sep-2016
PublisherNature Publishing Group
CitationNature Communications 7: 12761 (2016)
AbstractSmall-molecule fragments binding to biomacromolecules can be starting points for the development of drugs, but are often difficult to detect due to low affinities. Here we present a strategy that identifies protein-binding fragments through their potential to induce the target-guided formation of covalently bound, irreversible enzyme inhibitors. A protein-binding nucleophile reacts reversibly with a bis-electrophilic warhead, thereby positioning the second electrophile in close proximity of the active site of a viral protease, resulting in the covalent de-activation of the enzyme. The concept is implemented for Coxsackie virus B3 3C protease, a pharmacological target against enteroviral infections. Using an aldehyde-epoxide as bis-electrophile, active fragment combinations are validated through measuring the protein inactivation rate and by detecting covalent protein modification in mass spectrometry. The structure of one enzyme-inhibitor complex is determined by X-ray crystallography. The presented warhead activation assay provides potent non-peptidic, broad-spectrum inhibitors of enteroviral proteases.
Publisher version (URL)https://www.doi.org/10.1038/ncomms12761
URIhttp://hdl.handle.net/10261/160197
Identifiersdoi: 10.1038/ncomms12761
issn: 2041-1723
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