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 knockout or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with subnanomolar activity (K i = 370 ± 40 pM) and a high stability (t 1/2 > 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 ferricchloride-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.

Establishment and Evaluation of a Rat Model of Extracorporeal Membrane Oxygenation (ECMO) Thrombosis Using a 3D-printed Mock Oxygenator

“…This observation is typically attributed to platelets adhering to the circuit and oxygenator surfaces [35] and damage or activation by the pump [36]. However, emerging studies suggest that this effect may not be due to gross thrombus formation in the ECMO circuit [8,10]. This rat ECMO study is thus consistent with these studies' suggestion that the degree of thrombocytopenia does not appear to be related to the degree of thrombus formation.…”

Strategies to expand peptide functionality through hybridisation with a small molecule component

“…Such libraries have been used successfully to identify binders of a wide range of proteins including plasma kallikrein, 31,35 urokinase, 36 b-catenin, 37 and coagulation factor XII. 38 Additionally, these libraries can be used to develop chemical probes with the incorporation of a photoswitching motif, as discussed in Section 2.3. Recently, the approach has been modified to introduce protease pressure during selection, with the aim of identifying therapeutic peptides that are resistant to gastrointestinal proteases after oral administration.…”

A felületaktivált XII-es véralvadási faktor életkortól függő lehetséges szerepe a „bradikininvihar” kialakításában COVID–19-betegekben

“…Ez az összefüggés azért fontos, mert ennek értelmében a XII-es faktor aktivitását gátló gyógyszerek és kezelések hatékonyak lehetnek a COVID-19 súlyos tüneteinek (tüdőgyulladás, hypotonia és hypercoagulopathia) megelőzésében vagy gyógyításában. Ilyen hatású molekulák keresése is több irányban folyik [20]. Ugyanakkor már klinikai kipróbálás alatt állnak eljárások, kezelési formák, melyek alkalmasak lehetnek ezen útvonal gátlásával a COVID-19 tüneteinek enyhítésére.…”