Peptide macrocycle inhibitor of coagulation factor XII with subnanomolar affinity and high target selectivity.

Middendorp, Simon Jan; Wilbs, Jonas; Quarroz, Claudia; Calzavarini, Sara; Angelillo-Scherrer, Anne; Heinis, Christian (2017). Peptide macrocycle inhibitor of coagulation factor XII with subnanomolar affinity and high target selectivity. Journal of medicinal chemistry, 60(3), pp. 1151-1158. American Chemical Society 10.1021/acs.jmedchem.6b01548

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene)

UniBE Contributor:

Quarroz, Claudia; Calzavarini, Sara and Angelillo, Anne

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Katrin Kölliker-Schütz

Date Deposited:

13 Apr 2017 11:47

Last Modified:

04 Jan 2018 02:30

Publisher DOI:

10.1021/acs.jmedchem.6b01548

PubMed ID:

28045547

Uncontrolled Keywords:

Quarroz Claudia, Calzavarini Sara, Angelillo-Scherrer Anne

BORIS DOI:

10.7892/boris.93144

URI:

https://boris.unibe.ch/id/eprint/93144

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