Objekt-Metadaten

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, Joerg

HaupttitelIrreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments
AutorBecker, Daniel
AutorKaczmarska, Zuzanna
AutorArkona, Christoph
AutorSchulz, Robert
AutorTauber, Carolin
AutorWolber, Gerhard
AutorHilgenfeld, Rolf
AutorColl, Miquel
AutorRademann, Joerg
Seitenzahl9 S.
Freie SchlagwörterDrug discovery and development; High-throughput screening; Proteases; Viral infection
DDC615 Pharmakologie, Therapie
Auch erschienen inature Communications. - 7 (2016), Artikel Nr. 12761
ZusammenfassungSmall-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.
Dokumente
PDF-Datei von FUDOCS_document_000000025729
Falls Ihr Browser eine Datei nicht öffnen kann, die Datei zuerst herunterladen und dann öffnen.
 
Fachbereich/EinrichtungFB Biologie, Chemie, Pharmazie
Erscheinungsjahr2016
Dokumententyp/-SammlungenWissenschaftlicher Artikel
SpracheEnglisch
RechteCreative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Anmerkungen des AutorsDer Artikel wurde in einer reinen Open-Access-Zeitschrift publiziert.
Erstellt am23.11.2016 - 13:29:33
Letzte Änderung23.11.2016 - 13:29:37
 
Statische URLhttp://edocs.fu-berlin.de/docs/receive/FUDOCS_document_000000025729
DOI10.1038/ncomms12761
Zugriffsstatistik
 

LOADING...