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Becker D, Kaczmarska Z, Arkona C, et al. Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments. Nat Commun. 2016;7:12761doi: 10.1038/ncomms12761.
Becker, D., Kaczmarska, Z., Arkona, C., Schulz, R., Tauber, C., Wolber, G., Hilgenfeld, R., Coll, M., & Rademann, J. (2016). Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments. Nature communications, 712761. https://doi.org/10.1038/ncomms12761
Becker, Daniel, et al. "Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments." Nature communications vol. 7 (2016): 12761. doi: https://doi.org/10.1038/ncomms12761
Becker D, Kaczmarska Z, Arkona C, Schulz R, Tauber C, Wolber G, Hilgenfeld R, Coll M, Rademann J. Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments. Nat Commun. 2016 Sep 28;7:12761. doi: 10.1038/ncomms12761. PMID: 27677239; PMCID: PMC5052702.
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Nat Commun. 2016 Sep 28;7:12761. doi: 10.1038/ncomms12761.

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

Nature communications

Daniel Becker, Zuzanna Kaczmarska, Christoph Arkona, Robert Schulz, Carolin Tauber, Gerhard Wolber, Rolf Hilgenfeld, Miquel Coll, Jörg Rademann

Affiliations

  1. Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany.
  2. Institute for Research in Biomedicine, Parc Científic de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
  3. Institut de Biologia Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
  4. Institute of Biochemistry, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
  5. German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel Site, University of Lübeck, 23562 Lübeck, Germany.

PMID: 27677239 PMCID: PMC5052702 DOI: 10.1038/ncomms12761

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.

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