2024-03-28T15:46:27Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1601972021-12-28T15:58:28Zcom_10261_41com_10261_1col_10261_294
Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments
Becker, Daniel
Kaczmarska, Zuzanna
Arkona, Christoph
Schulz, Robert
Tauber, Carolin
Wolber, Gerhard
Hilgenfeld, Rolf
Coll, Miquel
Rademann, Jörg
European Commission
German Research Foundation
Ministerio de Economía y Competitividad (España)
Generalitat de Catalunya
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.
2018-02-06T10:21:55Z
2018-02-06T10:21:55Z
2016-09-28
2018-02-06T10:21:55Z
artículo
Nature Communications 7: 12761 (2016)
http://hdl.handle.net/10261/160197
10.1038/ncomms12761
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100001659
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100002809
27677239
eng
Publisher's version
https://www.doi.org/10.1038/ncomms12761
Sí
http://creativecommons.org/licenses/by/4.0/
openAccess
Nature Publishing Group