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Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.

ABSTRACT: Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity (Ki?=?370?±?40?pM) and a high stability (t1/2?>?5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899?Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs. We found that it reduces ferric-chloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions.

SUBMITTER: Wilbs J

PROVIDER: S-EPMC7403315 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.

Wilbs Jonas J Kong Xu-Dong XD Middendorp Simon J SJ Prince Raja R Cooke Alida A Demarest Caitlin T CT Abdelhafez Mai M MM Roberts Kalliope K Umei Nao N Gonschorek Patrick P Lamers Christina C Deyle Kaycie K Rieben Robert R Cook Keith E KE Angelillo-Scherrer Anne A Heinis Christian C

Nature communications 20200804 1

Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity (K<sub>i</sub> = 370 ± 40 pM) and a high stability (t<sub>1/2</sub> > 5 days in plasma), allowing for the preclinical e ...[more]

PMID: 32753636

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Project description:The ubiquitin-proteasome system is an essential regulator of many cellular processes including controlling protein homeostasis. The degradation of proteins by the multi-subunit proteasome complex is tightly regulated through a series of checkpoints, amongst which are a set of deubiquitinating proteases (DUBs). The proteasome-associated DUBs, UCH-L5 (Ubiquitin carboxyl-terminal hydrolase isozyme L5) and USP14 (Ubiquitin-specific protease 14), and the integral-DUB in the proteasome, Rpn11, is known to regulate proteasomal degradation by deubiquitination of distinct substrates. Although selective inhibitors for USP14 and Rpn11 have been recently developed, there are no known inhibitors that selectively bind to UCH-L5. The X-ray structure of the Ubiquitin (Ub) bound to UCH-L5 shows a β-sheet hairpin in Ub that contains a crucial hydrophobic patch involved in the interaction with UCH-L5. Herein, we designed and developed both a Ub sequence-based linear- and cyclic- β-sheet hairpin peptide that was found to preferably inhibit UCH-L5. We show that these peptides have low micromolar IC50 values and the cyclic peptide competes with the activity-based UbVME (Ubiquitin-Vinyl-Methyl-Ester) probe for UCH-L5, binding in a concentration-dependent manner. We further establish the selectivity profile of the cyclic peptide for UCH-L5 compared to other members of the UCH-DUB family and other cysteine DUBs in cell lysate. Furthermore, the cyclic peptide infiltrated cells resulting in the accumulation of polyUb chains, and was found to be non-toxic at the concentrations used here. Taken together, our data suggest that the cyclic peptide permeates the cell membrane, inhibits UCH-L5 by possibly blocking its deubiquitinating function, and contributes to the accumulation of polyubiquitinated substrates. The implications of inhibiting UCH-L5 in the context of the 26S proteasome render it an attractive candidate for further development as a potential selective inhibitor for therapeutic purposes.

Dataset Information

Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.

Publications

Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.

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