Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity.
- Middendorp SJ Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
- Wilbs J Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
- Quarroz C University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, University of Bern, Inselspital, CH-3010 Bern, Switzerland.
- Calzavarini S University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, University of Bern, Inselspital, CH-3010 Bern, Switzerland.
- Angelillo-Scherrer A University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, University of Bern, Inselspital, CH-3010 Bern, Switzerland.
- Heinis C Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
- 2017-01-04
Published in:
- Journal of medicinal chemistry. - 2017
English
Factor XII (FXII) is a plasma protease that has emerged in recent years as a potential target to treat or prevent pathological thrombosis, to inhibit contact activation in extracorporeal circulation, and to treat the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, the generation of small molecule inhibitors has been challenging. In this work, we have generated a potent and selective FXIIa inhibitor by optimizing a peptide macrocycle that was recently evolved by phage display (Ki = 0.84 ± 0.03 nM). A fluorine atom introduced in the para-position of phenylalanine enhanced the binding affinity as much as 10-fold. Furthermore, we improved the proteolytic stability by substituting the N-terminal arginine by norarginine. The resulting inhibitor combines high inhibitory affinity and selectivity with a good stability in plasma (Ki = 1.63 ± 0.18 nM, >27 000-fold selectivity, t1/2(plasma) =16 ± 4 h). The inhibitor efficiently blocked activation of the intrinsic coagulation pathway in human blood ex vivo.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1021/acs.jmedchem.6b01548
- PMID 28045547
- Persistent URL
- https://sonar.ch/global/documents/132072
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