Biochemical assay; Coumarin; Factor XIIa; Fragment-based drug discovery; Medical device-induced thrombosis; Serine proteinase inhibitors; factor XIIa inhibitor; Coumarins; Humans; Blood Coagulation; Coumarins/pharmacology; Coumarins/metabolism; Thrombosis; Pharmacology; Drug Discovery; Organic Chemistry; General Medicine
Abstract :
[en] Previously, we described weak coumarin inhibitors of factor XIIa, a promising target for artificial surface-induced thrombosis and various inflammatory diseases. In this work, we used fragment-based drug discovery approach to improve our coumarin series. First, we screened about 200 fragments for the S1 pocket. The S1 pocket of trypsin-like serine proteases, such as factor XIIa, is highly conserved and is known to drive a major part of the association energy. From the screening, we selected fragments displaying a micromolar activity and studied their selectivity on other serine proteases. Then, these fragments were merged to our coumarin templates, leading to the generation of nanomolar inhibitors. The mechanism of inhibition was further studied by mass spectrometry demonstrating the covalent binding through the formation of an acyl enzyme complex. The most potent compound was tested in plasma to evaluate its stability and efficacy on coagulation assays. It exhibited a plasmatic half-life of 1.9 h and a good selectivity for the intrinsic coagulation pathway over the extrinsic one.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège [BE] NARILIS - NAmur Research Institute for LIfe Sciences - UNamur [BE]
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Davoine, Clara ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Traina, Amandine; Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
Evrard, Jonathan; Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
Lanners, Steve; Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
Fillet, Marianne ; Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Pochet, Lionel ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium. Electronic address: lionel.pochet@unamur.be
Language :
English
Title :
Coumarins as factor XIIa inhibitors: Potency and selectivity improvements using a fragment-based strategy.
F.R.S.-FNRS - Fund for Scientific Research [BE] Fondation Léon Fredericq [BE]
Funding text :
C.D. received funding from the National Fund for Scientific Research (FNRS) grant 40000455 and Fondation Léon Frédéricq grant 2020-2021-30-C.F.F. L.P. received funding from the University of Namur FSR Grant L. POCHET-12/2021 . M.F. received funding from the University of Liège Fonds Spéciaux—Crédits facultaires ID 14758 . We gratefully acknowledge the contribution of Oliver Garot for his technical assistance.
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