4YHM

Reversal Agent for Dabigatran

4YHM の概要

• エントリーDOI: 10.2210/pdb4yhm/pdb
• 分子名称: aDabi-Fab2b heavy chain, aDabi-Fab2b light chain, N-[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl-beta-alanine, ... (4 entities in total)
• 機能のキーワード: antibody, dabigatran, pradaxa, antidote, reversal agent, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48203.81

構造登録者

Schiele, F.,Nar, H. (登録日: 2015-02-27, 公開日: 2016-01-13, 最終更新日: 2024-11-13)

主引用文献

Schiele, F.,van Ryn, J.,Litzenburger, T.,Ritter, M.,Seeliger, D.,Nar, H.
Structure-guided residence time optimization of a dabigatran reversal agent.
Mabs, 7:871-880, 2015

PubMed 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®) 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.

PubMed: 26047352
DOI: 10.1080/19420862.2015.1057364

実験手法

X-RAY DIFFRACTION (2.16 Å)