An in vivo strategy to counteract post-administration anticoagulant activity of azido-Warfarin.

Date publication

mai 2017

Journal

Nature communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr WAGNER Alain , Dr KREZEL Wojciech

Tous les auteurs :
Ursuegui S, Recher M, Krężel W, Wagner A

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/28524847

Résumé

Drugs, usually long acting and metabolically stable molecules, might be the source of adverse effects triggered by complex drug interactions, anaphylaxis and drug-induced coagulopathy. To circumvent this growing drug safety issue, we herein investigate the opportunity offered by bio-orthogonal chemistry for in vivo drug neutralization. We design a small-molecule anticoagulant drug (Warfarin) containing an azide group that acts as a safety pin. It allows drug deactivation and restoration of physiological coagulation via in vivo click reaction with a suitable cyclooctyne-based neutralizing agent. In this strategy, the new molecule formed by reaction of the drug and the antidote is deprived of biological activity and prone to fast renal clearance. This 'Click &Clear' approach lays ground for new strategies in designing drugs with switchable biophysical properties.

Mots clés

Animals, Anticoagulants, administration & dosage, Azides, administration & dosage, Chromatography, Liquid, Click Chemistry, Kidney, drug effects, Male, Mice, Inbred C57BL, Tandem Mass Spectrometry, Warfarin, administration & dosage

Référence

Nat Commun. 2017 May;8:15242