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- Title
Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction.
- Authors
Jaegle, Mike; Steinmetzer, Torsten; Rademann, Jörg
- 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 n m 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.
- Subjects
BLOOD coagulation; AMIDATION; LIGANDS (Chemistry); NUCLEAR magnetic resonance spectroscopy; SURFACE plasmon resonance
- Publication
Angewandte Chemie International Edition, 2017, Vol 56, Issue 13, p3718
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201611547