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

Daniel Becker, Zuzanna Kaczmarska, Christoph Arkona, Robert Schulz, Carolin Tauber, Gerhard Wolber, Rolf Hilgenfeld, Miquel Coll and Jörg Rademann ()
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Daniel Becker: Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin
Zuzanna Kaczmarska: Institute for Research in Biomedicine, Parc Científic de Barcelona
Christoph Arkona: Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin
Robert Schulz: Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin
Carolin Tauber: Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin
Gerhard Wolber: Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin
Rolf Hilgenfeld: Institute of Biochemistry, University of Lübeck
Miquel Coll: Institute for Research in Biomedicine, Parc Científic de Barcelona
Jörg Rademann: Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract Small-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.

Date: 2016
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DOI: 10.1038/ncomms12761

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