4YHL: Reversal Agent For Dabigatran

Citation:
Abstract
Novel oral anticoagulants are effective and safe alternatives to vitamin-K antagonists for anticoagulation therapy. However, anticoagulation therapy in general is associated with an elevated risk of bleeding. Idarucizumab is a reversal agent for the direct thrombin inhibitor, dabigatran etexilate (Pradaxa(R)) and is currently in Phase 3 studies. Here, we report data on the antibody fragment aDabi-Fab2, a putative backup molecule for idarucizumab. Although aDabi-Fab2 completely reversed effects of dabigatran in a rat model in vivo, we observed significantly reduced duration of action compared to idarucizumab. Rational protein engineering, based on the X-ray structure of aDabi-Fab2, led to the identification of mutant Y103W. The mutant had optimized shape complementarity to dabigatran while maintaining an energetically favored hydrogen bond. It displayed increased affinity for dabigatran, mainly driven by a slower off-rate. Interestingly, the increased residence time translated into longer duration of action in vivo. It was thus possible to further enhance the efficacy of aDabi-Fab2 based on rational design, giving it the potential to serve as a back-up candidate for idarucizumab.
PDB ID: 4YHLDownload
MMDB ID: 135367
PDB Deposition Date: 2015/2/27
Updated in MMDB: 2016/01
Experimental Method:
x-ray diffraction
Resolution: 2.09  Å
Source Organism:
Similar Structures:
Biological Unit for 4YHL: dimeric; determined by author and by software (PISA)
Molecular Components in 4YHL
Label Count Molecule
Proteins (2 molecules)
1
Adabi-fab2b Heavy Chain
Molecule annotation
1
Adabi-fab2b Light Chain
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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