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Jaegle M, Steinmetzer T, Rademann J. Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction. Angew Chem Int Ed Engl. 2017;56(13):3718-3722doi: 10.1002/anie.201611547.
Jaegle, M., Steinmetzer, T., & Rademann, J. (2017). Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction. Angewandte Chemie (International ed. in English), 56(13), 3718-3722. https://doi.org/10.1002/anie.201611547
Jaegle, Mike, et al. "Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction." Angewandte Chemie (International ed. in English) vol. 56,13 (2017): 3718-3722. doi: https://doi.org/10.1002/anie.201611547
Jaegle M, Steinmetzer T, Rademann J. Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction. Angew Chem Int Ed Engl. 2017 Mar 20;56(13):3718-3722. doi: 10.1002/anie.201611547. Epub 2017 Feb 15. PMID: 28199769; PMCID: PMC5363247.
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Angew Chem Int Ed Engl. 2017 Mar 20;56(13):3718-3722. doi: 10.1002/anie.201611547. Epub 2017 Feb 15.

Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction.

Angewandte Chemie (International ed. in English)

Mike Jaegle, Torsten Steinmetzer, Jörg Rademann

Affiliations

  1. Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195, Berlin, Germany.
  2. Philipps-Universität Marburg, Fachbereich Pharmazie, Institut für Pharmazeutische Chemie, Marbacher Weg 6, 35037, Marburg, Germany.

PMID: 28199769 PMCID: PMC5363247 DOI: 10.1002/anie.201611547

Abstract

Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained. The fragment ligation reaction was detected with high sensitivity by an enzyme activity assay and by mass spectrometry. The reaction progress and autoinhibition of the templated reaction by the formed ligation product were determined, and the structure of the protein-inhibitor complex was elucidated.

© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Keywords: amide bond formation; enzyme inhibitors; fragment-based drug discovery; peptide bond formation; protein-templated reactions

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