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, Jörg Rademann*

*Corresponding author for this work
6 Citations (Scopus)

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.

Original languageEnglish
Article number12761
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 28.09.2016

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