title: A specific antidote for dabigatran: functional and structural characterization.
abstract: Dabigatran etexilate is a direct thrombin inhibitor and used widely as an anticoagulant for the prevention of stroke in patients with atrial fibrillation. However, anticoagulation therapy can be associated with an increased risk of bleeding. Here, we present data on the identification, humanization, and in vitro pharmacology of an antidote for dabigatran (aDabi-Fab). The X-ray crystal structure of dabigatran in complex with the antidote reveals many structural similarities of dabigatran recognition compared with thrombin. By a tighter network of interactions, the antidote achieves an affinity for dabigatran that is ~350 times stronger than its affinity for thrombin. Despite the structural similarities in the mode of dabigatran binding, the antidote does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. In addition we demonstrate that the antidote rapidly reversed the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation. This is the first report of a specific antidote for a next-generation anticoagulant that may become a valuable tool in patients who require emergency procedures.
authors.affiliation: Structural Research Group, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schiele
authors.forename: Joanne
authors.initials: J
authors.lastname: van Ryn
authors.forename: Keith
authors.initials: K
authors.lastname: Canada
authors.forename: Corey
authors.initials: C
authors.lastname: Newsome
authors.forename: Eliud
authors.initials: E
authors.lastname: Sepulveda
authors.forename: John
authors.initials: J
authors.lastname: Park
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
authors.forename: Tobias
authors.initials: T
authors.lastname: Litzenburger
mesh_terms: D000818:Animals; D000931:Antidotes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000991:Antithrombins / Q000037:antagonists & inhibitors*; D001562:Benzimidazoles / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D000069604:Dabigatran; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors
chemical_list: D000931:Antidotes; D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran